83 results on '"Drug-discovery"'
Search Results
2. Tuberculosis Drug Discovery Estimation Process by Using Machine and Deep Learning Models
- Author
-
Campos, Michael S. Ramirez, Rodríguez, Diana C., Orjuela-Cañón, Alvaro D., Filipe, Joaquim, Editorial Board Member, Ghosh, Ashish, Editorial Board Member, Prates, Raquel Oliveira, Editorial Board Member, Zhou, Lizhu, Editorial Board Member, Orjuela-Cañón, Alvaro David, editor, Lopez, Jesus A, editor, and Arias-Londoño, Julián David, editor
- Published
- 2024
- Full Text
- View/download PDF
3. Methodical selected coptisine attenuates the malignancy of cholangiocarcinoma through the blockade of EGFR signalling
- Author
-
Jungwhoi Lee, Jungsul Lee, Woogwang Sim, and Jae-Hoon Kim
- Subjects
3-D docking modeling ,Coptisine ,EGFR ,Cholangiocarcinoma ,Drug-discovery ,Nutrition. Foods and food supply ,TX341-641 - Abstract
The aim of the present study is to provide a methodical platform for the development of lead compounds against cholangiocarcinoma. Coptisine was selected as a potential anti-cancer nominee from a pool of phytochemicals using an in silico 3-D docking screening technique and validated the anti-cancer effects against cholangiocarcinoma through the blockade of EGFR signaling depending on the cellular degradation. We also verified that coptisine had no cytotoxicity in different human normal cells when compared with the clinically approved anti-cancer drug, erlotinib. In vitro and in silico analyses revealed that coptisine can suppress the expression of various oncogenic molecules and administrating coptisine showed an anti-cholangiocarcinoma tumor growth or recurrence using in vivo models. Collectively, we propose that a well-organized methodical 3-D docking screening platform is an innovative technique for the discovery of anti-cancer drugs against malignant tumors, and coptisine might be a safe and effective anti-cancer reagent against cholangiocarcinoma.
- Published
- 2024
- Full Text
- View/download PDF
4. Structural and dynamic determinants for highly selective RET kinase inhibition reveal cryptic druggability
- Author
-
Moustafa A. Shehata, Julia Contreras, Ana Martín-Hurtado, Aurane Froux, Hossam Taha Mohamed, Ahmed A. El-Sherif, and Iván Plaza-Menacho
- Subjects
Protein kinases ,Oncogene ,Structure-function ,Targeted-therapies ,Drug-discovery ,Medicine (General) ,R5-920 ,Science (General) ,Q1-390 - Abstract
Introduction: The structural and dynamic determinants that confer highly selective RET kinase inhibition are poorly understood. Objectives: To explore the druggability landscape of the RET active site in order to uncover structural and dynamic vulnerabilities that can be therapeutically exploited. Methods: We apply an integrated structural, computational and biochemical approach in order to explore the druggability landscape of the RET active site. Results: We demonstrate that the that the druggability landscape of the RET active site is determined by the conformational setting of the ATP-binding (P-) loop and its coordination with the αC helix. Open and intermediate P-loop structures display additional druggable vulnerabilities within the active site that were not exploited by first generation RET inhibitors. We identify a cryptic pocket adjacent to the catalytic lysine formed by K758, L760, E768 and L772, that we name the post-lysine pocket, with higher druggability potential than the adenine-binding site and with important implications in the regulation of the phospho-tyrosine kinase activity. Crystal structure and simulation data show that the binding mode of highly-selective RET kinase inhibitors LOXO-292 and BLU-667 is controlled by a synchronous open P-loop and αC-in configuration that allows accessibility to the post-lysine pocket. Molecular dynamics simulations show that these inhibitors efficiently occupy the post-lysine pocket with high stability through the simulation time-scale (300 ns), with both inhibitors forming hydrophobic contacts further stabilized by pi-cation interactions with the catalytic K758. Engineered mutants targeting the post-lysine pocket impact on inhibitor binding and sensitivity, as well as RET tyrosine kinase activity. Conclusions: The identification of the post-lysine pocket as a new druggable vulnerability in the RET kinase and its exploitation by second generation RET inhibitors have important implications for future drug design and the development of personalized therapies for patients with RET-driven cancers.
- Published
- 2023
- Full Text
- View/download PDF
5. Collaboration Between the Patent System and Pharmaceutical Regulations for Drug-Discovery Innovation in Japan
- Author
-
Maeda, Takeshi, Hu, Yunfang, Series Editor, Hamori, Shigeyuki, Series Editor, Enomoto, Masahiro, Editorial Board Member, Fujioka, Yoshihide, Editorial Board Member, Kaneko, Yuka, Editorial Board Member, Suzuki, Kazumi, Editorial Board Member, Yamamoto, Kenji, Editorial Board Member, Negishi, Akira, editor, Wakui, Masako, editor, and Mariyama, Naoko, editor
- Published
- 2022
- Full Text
- View/download PDF
6. Structural and dynamic determinants for highly selective RET kinase inhibition reveal cryptic druggability.
- Author
-
Shehata, Moustafa A., Contreras, Julia, Martín-Hurtado, Ana, Froux, Aurane, Mohamed, Hossam Taha, El-Sherif, Ahmed A., and Plaza-Menacho, Iván
- Abstract
First-generation RET inhibitors were multi-tyrosine kinase inhibitors (TKIs) derived from secondary pharmacology targeting the adenine-binding pocket that resulted in poor clinical outputs. Recently developed second-generation RET inhibitors (primary pharmacology derived) exploit in addition further vulnerabilities within the active site e.g. the post-lysine pocket (PKP). We define the structural and dynamical determinants conferring high selectivity to these inhibitors agaisnt RET by targeting the PKP, making them clinically successful. [Display omitted] • The druggability landscape of the RET active site is determined by the structural dynamics of the P-loop and the αC helix. • RET selectivity is achieved by the occupancy of a small cryptic pocket adjacent to catalytic lysine defined by K758, L760, E768 and L772: the post-lysine pocket. • Efficient occupancy of the post-lysine pocket is restricted to a synchronous P-loop open and αC-in configuration, a distinctive feature of RET crystal structures. • LOXO-292 and BLU-667 target the post-lysine pocket and exploit extensive ATP mimicry. • Engineered mutants targeting the post-lysine pocket impact on inhibitor binding and sensitivity, as well as RET tyrosine kinase activity. The structural and dynamic determinants that confer highly selective RET kinase inhibition are poorly understood. To explore the druggability landscape of the RET active site in order to uncover structural and dynamic vulnerabilities that can be therapeutically exploited. We apply an integrated structural, computational and biochemical approach in order to explore the druggability landscape of the RET active site. We demonstrate that the that the druggability landscape of the RET active site is determined by the conformational setting of the ATP-binding (P-) loop and its coordination with the αC helix. Open and intermediate P-loop structures display additional druggable vulnerabilities within the active site that were not exploited by first generation RET inhibitors. We identify a cryptic pocket adjacent to the catalytic lysine formed by K758, L760, E768 and L772, that we name the post-lysine pocket, with higher druggability potential than the adenine-binding site and with important implications in the regulation of the phospho-tyrosine kinase activity. Crystal structure and simulation data show that the binding mode of highly-selective RET kinase inhibitors LOXO-292 and BLU-667 is controlled by a synchronous open P-loop and αC-in configuration that allows accessibility to the post-lysine pocket. Molecular dynamics simulations show that these inhibitors efficiently occupy the post-lysine pocket with high stability through the simulation time-scale (300 ns), with both inhibitors forming hydrophobic contacts further stabilized by pi-cation interactions with the catalytic K758. Engineered mutants targeting the post-lysine pocket impact on inhibitor binding and sensitivity, as well as RET tyrosine kinase activity. The identification of the post-lysine pocket as a new druggable vulnerability in the RET kinase and its exploitation by second generation RET inhibitors have important implications for future drug design and the development of personalized therapies for patients with RET-driven cancers. [ABSTRACT FROM AUTHOR]
- Published
- 2023
- Full Text
- View/download PDF
7. The next generation of drug resistant tuberculosis drug design.
- Author
-
Singh V
- Published
- 2025
- Full Text
- View/download PDF
8. TriTOX: A novel Trichomonas vaginalis assay platform for high-throughput screening of compound libraries
- Author
-
Alexander Y.F. Lam, Daniel Vuong, Aaron R. Jex, Andrew M. Piggott, Ernest Lacey, and Samantha J. Emery-Corbin
- Subjects
Trichomonas ,Tritrichomonas ,Drug-discovery ,Natural products ,Microbial metabolites ,Infectious and parasitic diseases ,RC109-216 - Abstract
Trichomonas vaginalis is a neglected urogenital parasitic protist that causes 170 million cases of trichomoniasis annually, making it the most prevalent non-viral, sexually transmitted disease. Trichomoniasis treatment relies on nitroheterocyclics, such as metronidazole. However, with increasing drug-resistance, there is an urgent need for novel anti-trichomonals. Little progress has been made to translate anti-trichomonal research into commercialised therapeutics, and the absence of a standardised compound-screening platform is the immediate stumbling block for drug-discovery. Herein, we describe a simple, cost-effective growth assay for T. vaginalis and the related Tritrichomonas foetus. Tracking changes in pH were a valid indicator of trichomonad growth (T. vaginalis and T. foetus), allowing development of a miniaturised, chromogenic growth assay based on the phenol red indicator in 96- and 384-well microtiter plate formats. The outputs of this assay can be quantitatively and qualitatively assessed, with consistent dynamic ranges based on Z′ values of 0.741 and 0.870 across medium- and high-throughput formats, respectively. We applied this high-throughput format within the largest pure-compound microbial metabolite screen (812 compounds) for T. vaginalis and identified 43 hit compounds. We compared these identified compounds to mammalian cell lines, and highlighted extensive overlaps between anti-trichomonal and anti-tumour activity. Lastly, observing nanomolar inhibition of T. vaginalis by fumagillin, and noting this compound has reported activity in other protists, we performed in silico analyses of the interaction of fumagillin with its molecular target methionine aminopeptidase 2 for T. vaginalis, Giardia lamblia and Entamoeba histolytica, highlighting potential for fumagillin as a broad-spectrum anti-protistal against microaerophilic protists. Together, this new platform will accelerate drug-discovery efforts, underpin drug-resistance screening in trichomonads, and contributing to a growing body of evidence highlighting the potential of microbial natural products as novel anti-protistals.
- Published
- 2021
- Full Text
- View/download PDF
9. Synthesis, Characterization and Complex Evaluation of Antibacterial Activity and Cytotoxicity of New Arylmethylidene Ketones and Pyrimidines with Camphane Skeletons.
- Author
-
Slavchev, Ivaylo M., Mitrev, Yavor, Shivachev, Boris, Valcheva, Violeta, Dogonadze, Marine, Solovieva, Natalia, Vyazovaya, Anna, Mokrousov, Igor, Link, Wolfgang, Jiménez, Lucía, Cautain, Bastien, Mackenzie, Thomas A., Portugal, Isabel, Lopes, Francisca, Capela, Rita, Perdigão, João, and Dobrikov, Georgi M.
- Subjects
- *
ANTIBACTERIAL agents , *KETONES , *SCHIFF bases , *MYCOBACTERIUM tuberculosis , *PYRIMIDINES , *PATHOGENIC bacteria , *SKELETON - Abstract
The synthesis of 20 arylidenecamphors and 15 pyrimidines with camphane skeleton is described in the current report. A modified method for preparation of sterically hindered 2‐aminopyrimidines in two steps was demonstrated. The evaluation of their in vitro activity against Mycobacterium tuberculosis H37Rv showed different MIC values (up to 0.91 μM for ketone 39). Compound 35 demonstrated moderate (8.23 μM), but sustainable activity toward a collection of drug‐resistant M. tuberculosis strains. Many of the compounds (especially among 2‐aminopyridines 42–56) exhibited good to excellent activity against different strains of pathogenic bacteria and fungi (MIC up to 0.60 μM for compound 50), compared with reference antibiotics. Many of the newly designed compounds possess also in vitro cytotoxicity. [ABSTRACT FROM AUTHOR]
- Published
- 2022
- Full Text
- View/download PDF
10. From cells to atoms: Cryo‐EM as an essential tool to investigate pathogen biology, host–pathogen interaction, and drug discovery.
- Author
-
Shepherd, Doulin C., Dalvi, Somavally, and Ghosal, Debnath
- Subjects
- *
COVID-19 , *SARS-CoV-2 , *CYTOLOGY , *DRUG discovery - Abstract
Electron cryo‐microscopy (cryo‐EM) has lately emerged as a powerful method in structural biology and cell biology. While cryo‐EM single‐particle analysis (SPA) is now routinely delivering structures of purified proteins and protein complexes at near‐atomic resolution, the use of electron cryo‐tomography (cryo‐ET), together with subtomogram averaging, is allowing visualization of macromolecular complexes in their native cellular environment, at unprecedented resolution. The unique ability of cryo‐EM to provide information at many spatial resolution scales from ångströms to microns makes it an invaluable tool that bridges the classic "resolution‐gap" between structural biology and cell biology domains. Like in many other fields of biology, in recent years, cryo‐EM has revolutionized our understanding of pathogen biology, host–pathogen interaction and has made significant strides toward structure‐based drug discovery. In a very recent example, during the ongoing coronavirus disease (COVID‐19) pandemic, the structure of the stabilized severe acute respiratory syndrome coronavirus 2 (SARS‐CoV‐2) spike protein was deciphered by SPA. This led to the development of multiple vaccines. Alongside, cryo‐ET provided key insights into the structure of the native virion, mechanism of its entry, replication, and budding; demonstrating the unrivaled power of cryo‐EM in investigating pathogen biology, host–pathogen interaction, and drug discovery. In this review, we showcase a few examples of how different imaging modalities within cryo‐EM have enabled the study of microbiology and host–pathogen interaction. [ABSTRACT FROM AUTHOR]
- Published
- 2022
- Full Text
- View/download PDF
11. Synthesis and activity of benzimidazole N-Acylhydrazones against Trypanosoma cruzi, Leishmania amazonensis and Leishmania infantum.
- Author
-
Ramos, Laís G., de Souza, Kátia R., Barbosa, Juliana M.C., Salomão, Kelly, Sales Junior, Policarpo A., Pereira, Valéria R.A., Murta, Silvane M.F., Ferreira, Rafaela S., Bernardes, Talita C.D., Wardell, Solange M.S.V., Wardell, James L., Boechat, Nubia, and Carvalho, Samir A.
- Subjects
- *
LEISHMANIA , *TRYPANOSOMA cruzi , *BENZIMIDAZOLES , *LEISHMANIA infantum , *ANTIPROTOZOAL agents , *SPECIES - Abstract
[Display omitted] • Planning of new Benzimidazole N- acylhydrazones with antitrypanosomal activity. • Biological evaluation of the compounds against T. cruzi strains (Y and Tulahuen) • Biological evaluation of the compounds against L. amazonensis and L. infantum. In this study, we present the design, synthesis, and cytotoxic evaluation of a series of benzimidazole N -acylhydrazones against strains of T. cruzi (Y and Tulahuen) and Leishmania species (L. amazonensis and L. infantum). Compound (E)- N '-((5-Nitrofuran-2-yl)methylene)-1 H -benzo[ d ]imidazole-2-carbohydrazide demonstrated significant activity against both trypomastigote and amastigote forms (Tulahuen strain), with an IC 50 /120 h of 0.033 μM and a selectivity index (SI) of 7680. This represents a potency 46 times greater than that of benznidazole (IC 50 /120 h = 1.520 μM, SI = 1390). Another compound (E)- N '-(2-Hydroxybenzylidene)-1 H -benzo[ d ]imidazole-2-carbohydrazide showed promising activity against both trypomastigote and amastigote forms (Tulahuen strain), with an IC 50 /120 h of 3.600 μM and an SI of 14.70. However, its efficacy against L. infantum and L. amazonensis was comparatively lower. These findings provide valuable insights for the development of more effective treatments against Trypanosoma cruzi. [ABSTRACT FROM AUTHOR]
- Published
- 2024
- Full Text
- View/download PDF
12. Implications of Fragment-Based Drug Discovery in Tuberculosis and HIV
- Author
-
Mohan Krishna Mallakuntla, Namdev S. Togre, Destiny B. Santos, and Sangeeta Tiwari
- Subjects
fragment-based drug design ,drug-discovery ,structure-based drug design ,mycobacterium tuberculosis ,HIV ,Medicine ,Pharmacy and materia medica ,RS1-441 - Abstract
Tuberculosis (TB) remains a global health problem and the emergence of HIV has further worsened it. Long chemotherapy and the emergence of drug-resistance strains of Mycobacterium tuberculosis as well as HIV has aggravated the problem. This demands urgent the need to develop new anti-tuberculosis and antiretrovirals to treat TB and HIV. The lack of diversity in drugs designed using traditional approaches is a major disadvantage and limits the treatment options. Therefore, new technologies and approaches are required to solve the current issues and enhance the production of drugs. Interestingly, fragment-based drug discovery (FBDD) has gained an advantage over high-throughput screenings as FBDD has enabled rapid and efficient progress to develop potent small molecule compounds that specifically bind to the target. Several potent inhibitor compounds of various targets have been developed using FBDD approach and some of them are under progression to clinical trials. In this review, we emphasize some of the important targets of mycobacteria and HIV. We also discussed about the target-based druggable molecules that are identified using the FBDD approach, use of these druggable molecules to identify novel binding sites on the target and assays used to evaluate inhibitory activities of these identified druggable molecules on the biological activity of the targets.
- Published
- 2022
- Full Text
- View/download PDF
13. TriTOX: A novel Trichomonas vaginalis assay platform for high-throughput screening of compound libraries.
- Author
-
Lam, Alexander Y.F., Vuong, Daniel, Jex, Aaron R., Piggott, Andrew M., Lacey, Ernest, and Emery-Corbin, Samantha J.
- Abstract
Trichomonas vaginalis is a neglected urogenital parasitic protist that causes 170 million cases of trichomoniasis annually, making it the most prevalent non-viral, sexually transmitted disease. Trichomoniasis treatment relies on nitroheterocyclics, such as metronidazole. However, with increasing drug-resistance, there is an urgent need for novel anti-trichomonals. Little progress has been made to translate anti-trichomonal research into commercialised therapeutics, and the absence of a standardised compound-screening platform is the immediate stumbling block for drug-discovery. Herein, we describe a simple, cost-effective growth assay for T. vaginalis and the related Tritrichomonas foetus. Tracking changes in pH were a valid indicator of trichomonad growth (T. vaginalis and T. foetus), allowing development of a miniaturised, chromogenic growth assay based on the phenol red indicator in 96- and 384-well microtiter plate formats. The outputs of this assay can be quantitatively and qualitatively assessed, with consistent dynamic ranges based on Z′ values of 0.741 and 0.870 across medium- and high-throughput formats, respectively. We applied this high-throughput format within the largest pure-compound microbial metabolite screen (812 compounds) for T. vaginalis and identified 43 hit compounds. We compared these identified compounds to mammalian cell lines, and highlighted extensive overlaps between anti-trichomonal and anti-tumour activity. Lastly, observing nanomolar inhibition of T. vaginalis by fumagillin, and noting this compound has reported activity in other protists, we performed in silico analyses of the interaction of fumagillin with its molecular target methionine aminopeptidase 2 for T. vaginalis , Giardia lamblia and Entamoeba histolytica , highlighting potential for fumagillin as a broad-spectrum anti-protistal against microaerophilic protists. Together, this new platform will accelerate drug-discovery efforts, underpin drug-resistance screening in trichomonads, and contributing to a growing body of evidence highlighting the potential of microbial natural products as novel anti-protistals. [Display omitted] [ABSTRACT FROM AUTHOR]
- Published
- 2021
- Full Text
- View/download PDF
14. Zebrafish Neurobehavioral Assays for Drug Addiction Research
- Author
-
Schneider, Henning and Kalueff, Allan V., editor
- Published
- 2017
- Full Text
- View/download PDF
15. Fragment-Based Drug Discovery Targeting the T-Box Riboswitch
- Author
-
Craig, Braeden C.
- Subjects
- Biochemistry, Chemistry, Drug-discovery, Computational, Docking, Riboswitch, RNA, T-Box
- Abstract
Due to the ever-growing health concern of antibiotic resistance, there is a need for novel drug development that can target bacteria in a way that is not resisted. In Gram positive bacteria, one of these potential targets is the T-box Riboswitch, which is a regulatory, non-coding region of RNA involved in amino acid regulation. Within the T-box Riboswitch is an antiterminator region, which dictates whether or not the downstream genes are transcribed. The genes that are regulated by the T-box riboswitch are directly involved in protein synthesis. The antiterminator is stabilized by the binding of uncharged tRNA, and when unbound forms the more stable terminator form, in which transcription is terminated. Drug design can be employed to target the antiterminator to prevent antitermination from occurring and cause the bacterial cell to die due to lack of protein synthesis. This thesis explores fragment-based computational docking studies to determine compounds that bind to the antiterminator with specificity and in regions that could potentially result in an inhibitory effect on antitermination. A compound library of 180 amino acid R groups were prepared and docked to the antiterminator as well as a control model without the tRNA-binding bulge region. Of the initial 180 amino acid R groups, 47 were determined to bind to the antiterminator in regions that may lead to inhibition with more specificity than in the control model. Additionally, 10 peptide links that were produced from these 47 compounds were further docked and each showed some level of binding to the regions of interest in the antiterminator. The results of this project indicated 47 amino acids that could potentially be used as building blocks for drug synthesis, in addition to 10 peptides that may produce an inhibitory effect on the antiterminator. Further studies can be performed on these compounds, such as fluorescence assays and transcriptional assays, to further test binding specificity and to determine if the compounds have the desired physiological outcome on the T-box riboswitch.
- Published
- 2024
16. Methodical selected coptisine attenuates the malignancy of cholangiocarcinoma through the blockade of EGFR signalling.
- Author
-
Lee, Jungwhoi, Lee, Jungsul, Sim, Woogwang, and Kim, Jae-Hoon
- Abstract
[Display omitted] • This is the first report to verify the attentively selected coptisine as a safety anti-cholangiocarcinoma reagent. • Coptisine attenuates the malignancy of cholangiocarcinoma via blockade of the EGFR signalling pathway mediating the cellular degradation. • Coptisine treatment has no cytotoxicity in different human normal cells compared with that of anti-cancer drug, erlotinib. • In vivo administrating coptisine shows significant anti-cholangiocarcinoma effects in tumor growth and recurrence xenograft models. • Methodical platform including 3-D modeling is optimal for discovering safety anti-cancer reagent. The aim of the present study is to provide a methodical platform for the development of lead compounds against cholangiocarcinoma. Coptisine was selected as a potential anti-cancer nominee from a pool of phytochemicals using an in silico 3-D docking screening technique and validated the anti-cancer effects against cholangiocarcinoma through the blockade of EGFR signaling depending on the cellular degradation. We also verified that coptisine had no cytotoxicity in different human normal cells when compared with the clinically approved anti-cancer drug, erlotinib. In vitro and in silico analyses revealed that coptisine can suppress the expression of various oncogenic molecules and administrating coptisine showed an anti-cholangiocarcinoma tumor growth or recurrence using in vivo models. Collectively, we propose that a well-organized methodical 3-D docking screening platform is an innovative technique for the discovery of anti-cancer drugs against malignant tumors, and coptisine might be a safe and effective anti-cancer reagent against cholangiocarcinoma. [ABSTRACT FROM AUTHOR]
- Published
- 2024
- Full Text
- View/download PDF
17. Actinomycetes - The Repertoire of Diverse Bioactive Chemical Molecules: From Structures to Antibiotics.
- Author
-
Baba IA, Wani ZA, Ali S, Ahmad Z, and Mubarak MM
- Abstract
The urgent need for novel antibiotics in the face of escalating global antimicrobial resistance necessitates innovative approaches to identify bioactive compounds. Actinomycetes, renowned for their prolific production of antimicrobial agents, stand as a cornerstone in this pursuit. Their diverse metabolites exhibit multifaceted bioactivities, including potent antituberculosis, anticancer, immunomodulatory, immuno-protective, antidiabetic, etc. Though terrestrial sources have been exploited significantly, contemporary developments in the field of antimicrobial drug discovery have put marine actinomycetes in a prominent light as a promising and relatively unexplored source of novel bioactive molecules. This is further boosted by post-genomic era advances like bioinformatics-based secretome analysis and reverse engineering that have totally revitalized actinomycetes antibiotic research. This review highlights actinomycetes-based chemically diverse scaffolds and clinically validated antibiotics along with the enduring significance of actinomycetes from untouched ecosystems, especially with recent advanced techniques in the quest for next-generation antimicrobials., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.net.)
- Published
- 2024
- Full Text
- View/download PDF
18. Vascular smooth muscle cell proliferation as a therapeutic target. Part 2: Natural products inhibiting proliferation.
- Author
-
Uhrin, Pavel, Wang, Dongdong, Mocan, Andrei, Waltenberger, Birgit, Breuss, Johannes M., Tewari, Devesh, Mihaly-Bison, Judit, Huminiecki, Łukasz, Starzyński, Rafał R., Tzvetkov, Nikolay T., Horbańczuk, Jarosław, and Atanasov, Atanas G.
- Subjects
- *
NATURAL products , *VASCULAR smooth muscle , *CELL proliferation , *ATHEROSCLEROSIS treatment , *DRUG development , *THERAPEUTICS - Abstract
Many natural products have been so far tested regarding their potency to inhibit vascular smooth muscle cell proliferation, a process involved in atherosclerosis, pulmonary hypertension and restenosis. Compounds studied in vitro and in vivo as VSMC proliferation inhibitors include, for example indirubin-3′-monoxime, resveratrol, hyperoside, plumericin, pelargonidin, zerumbone and apamin. Moreover, taxol and rapamycin, the most prominent compounds applied in drug-eluting stents to counteract restenosis, are natural products. Numerous studies show that natural products have proven to yield effective inhibitors of vascular smooth muscle cell proliferation and ongoing research effort might result in the discovery of further clinically relevant compounds. [ABSTRACT FROM AUTHOR]
- Published
- 2018
- Full Text
- View/download PDF
19. Early diagnosis and effective treatment regimens are the keys to tackle antimicrobial resistance in tuberculosis (TB): A report from Euroscicon's international TB Summit 2016.
- Author
-
Maitra, Arundhati, Kamil, Tengku Karmila, Shaik, Monisha, Danquah, Cynthia Amaning, Chrzastek, Alina, and Bhakta, Sanjib
- Subjects
- *
TUBERCULOSIS , *DRUG resistance , *ANTI-infective agents , *EARLY diagnosis , *LUNG diseases - Abstract
To say that tuberculosis (TB) has regained a strong foothold in the global human health and wellbeing scenario would be an understatement. Ranking alongside HIV/AIDS as the top reason for mortality due to a single infectious disease, the impact of TB extends far into socio-economic context worldwide. As global efforts led by experts and political bodies converge to mitigate the predicted outcome of growing antimicrobial resistance, the academic community of students, practitioners and researchers have mobilised to develop integrated, inter-disciplinary programmes to bring the plans of the former to fruition. Enabling this crucial requirement for unimpeded dissemination of scientific discovery was the TB Summit 2016, held in London, United Kingdom. This report critically discusses the recent breakthroughs made in diagnostics and treatment while bringing to light the major hurdles in the control of the disease as discussed in the course of the 3-day international event. Conferences and symposia such as these are the breeding grounds for successful local and global collaborations and therefore must be supported to expand the understanding and outreach of basic science research. [ABSTRACT FROM AUTHOR]
- Published
- 2017
- Full Text
- View/download PDF
20. Selective inhibitors of trypanosomal uridylyl transferase RET1 establish druggability of RNA post-transcriptional modifications.
- Author
-
Cording, Amy, Gormally, Michael, Bond, Peter J., Carrington, Mark, Balasubramanian, Shankar, Miska, Eric A., and Thomas, Beth
- Abstract
Non-coding RNAs are crucial regulators for a vast array of cellular processes and have been implicated in human disease. These biological processes represent a hitherto untapped resource in our fight against disease. In this work we identify small molecule inhibitors of a non-coding RNA uridylylation pathway. The TUTase family of enzymes is important for modulating non-coding RNA pathways in both human cancer and pathogen systems. We demonstrate that this new class of drug target can be accessed with traditional drug discovery techniques. Using theTrypanosoma bruceiTUTase, RET1, we identify TUTase inhibitors and lay the groundwork for the use of this new target class as a therapeutic opportunity for the under-served disease area of African Trypanosomiasis. In a broader sense this work demonstrates the therapeutic potential for targeting RNA post-transcriptional modifications with small molecules in human disease. [ABSTRACT FROM PUBLISHER]
- Published
- 2017
- Full Text
- View/download PDF
21. Small-molecule activators of a bacterial signaling pathway inhibit virulence.
- Author
-
Mansour KE, Qi Y, Yan M, Ramström O, Priebe GP, and Schaefers MM
- Abstract
The Burkholderia genus encompasses multiple human pathogens, including potential bioterrorism agents, that are often extensively antibiotic resistant. The FixLJ pathway in Burkholderia is a two-component system that regulates virulence. Previous work showed that fixLJ mutations arising during chronic infection confer increased virulence while decreasing the activity of the FixLJ pathway. We hypothesized that small-molecule activators of the FixLJ pathway could serve as anti-virulence therapies. Here, we developed a high-throughput assay that screened over 28,000 compounds and identified 11 that could specifically active the FixLJ pathway. Eight of these compounds, denoted B urkholderia Fix Activator (BFA) 1-8, inhibited the intracellular survival of Burkholderia in THP-1-dervived macrophages in a fixLJ -dependent manner without significant toxicity. One of the compounds, BFA1, inhibited the intracellular survival in macrophages of multiple Burkholderia species. Predictive modeling of the interaction of BFA1 with Burkholderia FixL suggests that BFA1 binds to the putative ATP/ADP binding pocket in the kinase domain, indicating a potential mechanism for pathway activation. These results indicate that small-molecule FixLJ pathway activators are promising anti-virulence agents for Burkholderia and define a new paradigm for antibacterial therapeutic discovery.
- Published
- 2023
- Full Text
- View/download PDF
22. Structural and dynamic determinants for highly selective RET kinase inhibition reveal cryptic druggability
- Author
-
Shehata, Moustafa A, Contreras, Julia, Martín-Hurtado, Ana, Froux, Aurane, Mohamed, Hossam Taha, El-Sherif, Ahmed A, Plaza-Menacho, Iván, Shehata, Moustafa A., El-Sherif, Ahmed A., Centro Nacional de Investigaciones Oncológicas (CNIO), and Instituto de Salud Carlos III
- Subjects
Multidisciplinary ,Protein kinases ,Drug-discovery ,Structure - Function ,Oncogene ,Targeted-therapies - Abstract
The structural and dynamic determinants for highly selective RET kinase inhibition are poorly understood. Here we demonstrate by applying an integrated structural, computational and biochemical approach that the druggability landscape of the RET active site is determined by the conformational setting of the ATP-binding (P-) loop and its coordination with the αC helix. Open and intermediate P-loop structures display additional druggable vulnerabilities within the active site that were not exploited by first generation RET inhibitors. We identify a cryptic pocket adjacent to the catalytic lysine formed by K758, L760, E768 and L772, that we name the post-lysine pocket, with higher druggability potential than the adenine-binding site and with important implications in the regulation of phospho-tyrosine kinase activity. Crystal structure and simulation data show that the binding mode of highly-selective RET kinase inhibitors LOXO-292 and BLU-667 is controlled by a synchronous open P-loop and αC-in configuration that allows accessibility to the post-lysine pocket. Molecular dynamics simulation show that these inhibitors efficiently occupy the post-lysine pocket with high stability through the simulation time-scale (300 ns), with both inhibitors forming hydrophobic contacts in the pocket further stabilized by pi-cation interactions with the catalytic K758. Engineered mutants targeting the post-lysine pocket impact on inhibitor binding and sensitivity, as well as RET tyrosine kinase activity. The identification of the post-lysine pocket as a cryptic druggable vulnerability in the RET kinase and its exploitation by second generation RET inhibitors has important implications for future drug design and the development of personalized therapies for patients with RET-driven cancers. We thank the Centro Nacional de Investigaciones Oncológicas (CNIO), which is supported by the Instituto de Salud Carlos III and recognized as a “Severo Ochoa” Centre of Excellence (ref. CEX2019-000891-S, awarded by MCIN/AEI/ 10.13039/501100011033) for core funding and supporting this study. This work was further supported by projects: BFU2017-86710-R funded by MCIN/ AEI /10.13039/501100011033 and ERDF “A way of making Europe”, PID2020-117580RB-I00 funded by MCIN/ AEI /10.13039/501100011033, RYC-2016-1938 funded by MCIN/AEI /10.13039/501100011033 and ESF “Investing in your future”, and a Marie Curie WHRI-ACADEMY International grant (number 608765) to IP-M and a CNIO-Friends predoctoral Carmen Gloria Bonnet Fellowship to MAS. No
- Published
- 2022
23. Hunting for Novel Routes in Anticancer Drug Discovery: Peptides against Sam-Sam Interactions.
- Author
-
Mercurio, Flavia Anna, Vincenzi, Marian, and Leone, Marilisa
- Subjects
- *
DRUG discovery , *PEPTIDES , *ANTINEOPLASTIC agents , *PROTEIN receptors , *PROTEIN binding , *ADAPTOR proteins - Abstract
Among the diverse protein binding modules, Sam (Sterile alpha motif) domains attract attention due to their versatility. They are present in different organisms and play many functions in physiological and pathological processes by binding multiple partners. The EphA2 receptor contains a Sam domain at the C-terminus (EphA2-Sam) that is able to engage protein regulators of receptor stability (including the lipid phosphatase Ship2 and the adaptor Odin). Ship2 and Odin are recruited by EphA2-Sam through heterotypic Sam-Sam interactions. Ship2 decreases EphA2 endocytosis and consequent degradation, producing chiefly pro-oncogenic outcomes in a cellular milieu. Odin, through its Sam domains, contributes to receptor stability by possibly interfering with ubiquitination. As EphA2 is upregulated in many types of tumors, peptide inhibitors of Sam-Sam interactions by hindering receptor stability could function as anticancer therapeutics. This review describes EphA2-Sam and its interactome from a structural and functional perspective. The diverse design strategies that have thus far been employed to obtain peptides targeting EphA2-mediated Sam-Sam interactions are summarized as well. The generated peptides represent good initial lead compounds, but surely many efforts need to be devoted in the close future to improve interaction affinities towards Sam domains and consequently validate their anticancer properties. [ABSTRACT FROM AUTHOR]
- Published
- 2022
- Full Text
- View/download PDF
24. Utilizing Ayurvedic literature for the identification of novel phytochemical inhibitors of botulinum neurotoxin A.
- Author
-
Yalamanchili, Chinni, Manda, Vamshi K., Chittiboyina, Amar G., Guernieri, Rebecca L., Jr.Harrell, William A., Webb, Robert P., Smith, Leonard A., and Khan, Ikhlas A.
- Subjects
- *
BOTULISM , *AYURVEDIC medicine , *ALTERNATIVE medicine , *BIOLOGICAL assay , *BOOKS , *BOTULINUM toxin , *CLOSTRIDIUM diseases , *COMPUTER simulation , *DRUG design , *FLAVONOIDS , *HIGH performance liquid chromatography , *PHYTOCHEMICALS , *DESCRIPTIVE statistics , *IN vitro studies , *DISEASE complications , *PREVENTION - Abstract
Ethnopharmacological relevance Ayurveda, an ancient holistic system of health care practiced on the Indian subcontinent, utilizes a number of multi-plant formulations and is considered by many as a potential source for novel treatments, as well as the identification of new drugs. Our aim is to identify novel phytochemicals for the inhibition of bacterial exotoxin, botulinum neurotoxin A (BoNT/A) based on Ayurvedic literature. BoNT/A is released by Clostridium species, which when ingested, inhibits the release of acetylcholine by concentrating at the neuromuscular junction and causes flaccid paralysis, resulting in a condition termed as botulism, and may also lead to death due to respiratory arrest. Methods Fifteen plants were selected from the book ‘Diagnosis and treatment of diseases in Ayurveda’ by Vaidya Bhagwan Dash and Lalitesh Kashyap, based on their frequency of use in the formulations used for the treatment of six diseases with neuromuscular symptoms similar to botulism. Phytochemicals from these plants were screened using in silico , and in vitro methods. Structures of 570 reported phytochemicals from 14 plants were docked inside six reported BoNT/A light chain crystal structures using ensemble docking module in Maestro (Schrödinger, LLE). Results From the docking scores and structural diversity, nine compounds including acoric acid 1 , three flavonoids, three coumarins derivatives, one kava lactone were selected and screened using an in vitro HPLC-based protease assay. The bioassay results showed that several compounds possess BoNT/A LC inhibition of 50–60% when compared to positive controls NSC 84094 and CB7967495 (80–95%). Conclusion Further testing of the active compounds identified from Ayurvedic literature and structure-activity studies of acoric acid 1 using more sensitive bioassays is under way. The identification of acoric acid 1 , a novel scaffold against BoNT/A, exemplifies the utility of Ayurvedic literature for the discovery of novel drug leads. [ABSTRACT FROM AUTHOR]
- Published
- 2017
- Full Text
- View/download PDF
25. Synthesis of two chiral octahydroindole scaffolds for drug discovery.
- Author
-
Sydnes, Magne O., Van Le, Phuc, Olschimke, Jens, Healy, Peter C., Garavelas, Agatha, Tajabadi, Fatemeh Mazraati, Pedro, Liliana, Quinn, Ronald J., and Jenkins, Ian D.
- Subjects
- *
CHEMICAL synthesis , *CHIRALITY , *INDOLE compounds , *DRUG development , *NATURAL products - Abstract
There are over one thousand natural products that contain the octahydroindole scaffold, which can be considered a biologically validated starting point for the design of compound libraries. Two chiral octahydroindole scaffolds have been synthesized in multigram quantities in two steps from a readily available indoline. They contain either one or two amino groups (one Boc-protected) and a protected carboxylic acid group, and have been designed for ease of conversion to a lead generation library. The structures of both scaffolds have been established unequivocally by single crystal X-ray structure determination. [ABSTRACT FROM AUTHOR]
- Published
- 2016
- Full Text
- View/download PDF
26. 2D and 3D similarity landscape analysis identifies PARP as a novel off-target for the drug Vatalanib.
- Author
-
Gohlke, Bjoern-Oliver, Overkamp, Tim, Richter, Anja, Richter, Antje, Daniel, Peter T., Gillissen, Bernd, and Preissner, Robert
- Subjects
- *
BIOINFORMATICS , *VASCULAR endothelial growth factors , *POLY ADP ribose , *DRUG side effects , *DRUG design - Abstract
Background: Searching for two-dimensional (2D) structural similarities is a useful tool to identify new active compounds in drug-discovery programs. However, as 2D similarity measures neglect important structural and functional features, similarity by 2D might be underestimated. In the present study, we used combined 2D and three-dimensional (3D) similarity comparisons to reveal possible new functions and/or side-effects of known bioactive compounds. Results: We utilised more than 10,000 compounds from the SuperTarget database with known inhibition values for twelve different anti-cancer targets. We performed all-against-all comparisons resulting in 2D similarity landscapes. Among the regions with low 2D similarity scores are inhibitors of vascular endothelial growth factor receptor (VEGFR) and inhibitors of poly ADP-ribose polymerase (PARP). To demonstrate that 3D landscape comparison can identify similarities, which are untraceable in 2D similarity comparisons, we analysed this region in more detail. This 3D analysis showed the unexpected structural similarity between inhibitors of VEGFR and inhibitors of PARP. Among the VEGFR inhibitors that show similarities to PARP inhibitors was Vatalanib, an oral "multi-targeted" small molecule protein kinase inhibitor being studied in phase-III clinical trials in cancer therapy. An in silico docking simulation and an in vitro HT universal colorimetric PARP assay confirmed that the VEGFR inhibitor Vatalanib exhibits off-target activity as a PARP inhibitor, broadening its mode of action. Conclusion: In contrast to the 2D-similarity search, the 3D-similarity landscape comparison identifies new functions and side effects of the known VEGFR inhibitor Vatalanib. [ABSTRACT FROM AUTHOR]
- Published
- 2015
- Full Text
- View/download PDF
27. Repurposing FDA approved drugs against the human fungal pathogen, Candida albicans.
- Author
-
Kim, Kevin, Zilbermintz, Leeor, and Martchenko, Mikhail
- Subjects
ANTIFUNGAL agents ,CANDIDA albicans ,CANDIDIASIS treatment ,DRUG therapy ,DRUG efficacy - Abstract
Background: The high cost and prolonged timeline of new drug discovery and development are major roadblocks to creating therapies for infectious diseases. Candida albicans is an opportunistic fungal pathogen that is the most common cause of fatal fungal infections in humans and costs $2-4 billion dollars to treat in the US alone. Methods: To accelerate drug discovery, we screened a library of 1581 existing FDA approved drugs, as well as drugs approved abroad, for inhibitors of C. albicans. The screen was done on YPD yeast growth media as well as on the serum plate assay developed in this study. Results: We discovered that fifteen drugs, all which were originally approved for treating various infectious and noninfectious diseases, were able to kill Candida albicans. Additionally, one of those drugs, Octodrine, displays wide-spectrum anti-microbial activity. Compared to other selected anti-Candida drugs, Octodrine was shown to be one of the most effective drugs in killing serum-grown Candida albicans without significantly affecting the survival of host macrophages and skin cells. Conclusions: This approach is useful for the discovery of economically viable new therapies against infectious diseases. [ABSTRACT FROM AUTHOR]
- Published
- 2015
- Full Text
- View/download PDF
28. Looking for SARS-CoV-2 Therapeutics Through Computational Approaches.
- Author
-
Vincenzi M, Mercurio FA, and Leone M
- Subjects
- Humans, Molecular Docking Simulation, Protease Inhibitors pharmacology, Antiviral Agents pharmacology, Antiviral Agents therapeutic use, Drug Repositioning, SARS-CoV-2, COVID-19
- Abstract
Background: In the last few years, in silico tools, including drug repurposing coupled with structure-based virtual screening, have been extensively employed to look for anti-COVID-19 agents., Objective: The present review aims to provide readers with a portrayal of computational approaches that could be conducted more quickly and cheaply to novel anti-viral agents. Particular attention is given to docking-based virtual screening., Methods: The World Health Organization website was consulted to gain the latest information on SARS-CoV-2, its novel variants and their interplay with COVID-19 severity and treatment options. The Protein Data Bank was explored to look for 3D coordinates of SARS-CoV-2 proteins in their free and bound states, in the wild-types and mutated forms. Recent literature related to in silico studies focused on SARS-CoV-2 proteins was searched through PubMed., Results: A large amount of work has been devoted thus far to computationally targeting viral entry and searching for inhibitors of the S-protein/ACE2 receptor complex. Another large area of investigation is linked to in silico identification of molecules able to block viral proteases -including Mpro- thus avoiding maturation of proteins crucial for virus life cycle. Such computational studies have explored the inhibitory potential of the most diverse molecule databases (including plant extracts, dietary compounds, FDA approved drugs)., Conclusion: More efforts need to be dedicated in the close future to experimentally validate the therapeutic power of in silico identified compounds in order to catch, among the wide ensemble of computational hits, novel therapeutics to prevent and/or treat COVID- 19., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.net.)
- Published
- 2023
- Full Text
- View/download PDF
29. Reversing radiation-induced immunosuppression using a new therapeutic modality.
- Author
-
Courtney CM, Sharma S, Fallgren C, Weil MM, Chatterjee A, and Nagpal P
- Subjects
- Mice, Animals, Humans, Recombinant Proteins pharmacology, Cytokines, Immunosuppression Therapy, Granulocyte Colony-Stimulating Factor pharmacology, Leukocytes, Mononuclear metabolism, Artificial Intelligence
- Abstract
Radiation-induced immune suppression poses significant health challenges for millions of patients undergoing cancer chemotherapy and radiotherapy treatment, and astronauts and space tourists travelling to outer space. While a limited number of recombinant protein therapies, such a Sargramostim, are approved for accelerating hematologic recovery, the pronounced role of granulocyte-macrophage colony-stimulating factor (GM-CSF or CSF2) as a proinflammatory cytokine poses additional challenges in creating immune dysfunction towards pathogenic autoimmune diseases. Here we present an approach to high-throughput drug-discovery, target validation, and lead molecule identification using nucleic acid-based molecules. These Nanoligomer™ molecules are rationally designed using a bioinformatics and an artificial intelligence (AI)-based ranking method and synthesized as a single-modality combining 6-different design elements to up- or downregulate gene expression of target gene, resulting in elevated or diminished protein expression of intended target. This method additionally alters related gene network targets ultimately resulting in pathway modulation. This approach was used to perturb and identify the most effective upstream regulators and canonical pathways for therapeutic intervention to reverse radiation-induced immunosuppression. The lead Nanoligomer™ identified in a screen of human donor derived peripheral blood mononuclear cells (PBMCs) upregulated Erythropoietin (EPO) and showed the greatest reversal of radiation induced cytokine changes. It was further tested in vivo in a mouse radiation-model with low-dose (3 mg/kg) intraperitoneal administration and was shown to regulate gene expression of epo in lung tissue as well as counter immune suppression. These results point to the broader applicability of our approach towards drug-discovery, and potential for further investigation of our lead molecule as reversible gene therapy to treat adverse health outcomes induced by radiation exposure., Competing Interests: Declaration of Competing Interest A.C., P.N., S.S., and C.M.C. are employed by the for-profit company Sachi Bioworks where this technology was developed. A.C. and P.N. are the founders of Sachi Bioworks, and P.N. has filed a patent on this technology., (Copyright © 2022. Published by Elsevier B.V.)
- Published
- 2022
- Full Text
- View/download PDF
30. Discovery of immunopotentiatory drugs: current and future strategies.
- Author
-
RHODES, J.
- Subjects
- *
IMMUNOLOGICAL adjuvants , *DRUG development - Abstract
Discusses the discovery of immunopotentiatory drugs. Processes in drug discovery; Candidates for immuniptentiatory drugs; Potential targets in the immune system for novel immunopotentiatory drugs.
- Published
- 2002
- Full Text
- View/download PDF
31. Small molecule neurolysin activators, potential multi-mechanism agents for ischemic stroke therapy.
- Author
-
Esfahani SH, Abbruscato TJ, Trippier PC, and Karamyan VT
- Subjects
- Brain metabolism, Humans, Metalloendopeptidases metabolism, Ischemic Stroke, Neuroprotective Agents, Stroke drug therapy
- Published
- 2022
- Full Text
- View/download PDF
32. Metabolomics-Driven Exploration of the Chemical Drug Space to Predict Combination Antimicrobial Therapies
- Author
-
Mattia Zampieri and Adrian I. Campos
- Subjects
epistasis ,Drug ,Prescription Drugs ,Combination therapy ,media_common.quotation_subject ,Computational biology ,Biology ,Article ,combination therapy ,03 medical and health sciences ,0302 clinical medicine ,Metabolomics ,Drug tolerance ,Drug Resistance, Multiple, Bacterial ,antibiotic ,Escherichia coli ,Metabolome ,Drug Interactions ,Molecular Biology ,high-throughput ,Repurposing ,030304 developmental biology ,media_common ,Internet ,0303 health sciences ,Drug discovery ,Cheminformatics ,Drug Repositioning ,Rational design ,Cell Biology ,E. coli ,metabolomics ,Anti-Bacterial Agents ,Drug Combinations ,Prestwick ,drug-discovery ,Gene Deletion ,Genome, Bacterial ,Metabolic Networks and Pathways ,030217 neurology & neurosurgery - Abstract
Summary Alternative to the conventional search for single-target, single-compound treatments, combination therapies can open entirely new opportunities to fight antibiotic resistance. However, combinatorial complexity prohibits experimental testing of drug combinations on a large scale, and methods to rationally design combination therapies are lagging behind. Here, we developed a combined experimental-computational approach to predict drug-drug interactions using high-throughput metabolomics. The approach was tested on 1,279 pharmacologically diverse drugs applied to the gram-negative bacterium Escherichia coli. Combining our metabolic profiling of drug response with previously generated metabolic and chemogenomic profiles of 3,807 single-gene deletion strains revealed an unexpectedly large space of inhibited gene functions and enabled rational design of drug combinations. This approach is applicable to other therapeutic areas and can unveil unprecedented insights into drug tolerance, side effects, and repurposing. The compendium of drug-associated metabolome profiles is available at https://zampierigroup.shinyapps.io/EcoPrestMet, providing a valuable resource for the microbiological and pharmacological communities., Graphical Abstract, Highlights • Metabolic profiling of E. coli response to 1,279 chemically diverse drugs • Large space of nonessential gene functions affected by human-targeted drugs • Genome-scale inference of drug targets and indirect mediators of drug response • Metabolome and chemogenomic profiling predict epistatic interactions between drugs, Campos and Zampieri monitor the metabolic response of E. coli to 1,279 drugs and reveal an unexpectedly large spectrum of metabolic effects. Combining metabolic profiling with chemogenomic data, they predict epistatic drug interactions and show how to expand the search for new antimicrobial treatments to compounds with no growth-inhibitory activity.
- Published
- 2019
- Full Text
- View/download PDF
33. Diabetic Complications: An Update on Pathobiology and Therapeutic Strategies.
- Author
-
Nellaiappan K, Preeti K, Khatri DK, and Singh SB
- Subjects
- Humans, Diabetes Mellitus, Diabetic Nephropathies etiology, Diabetic Nephropathies therapy, Diabetic Neuropathies etiology, Diabetic Neuropathies therapy, Diabetic Retinopathy etiology, Diabetic Retinopathy therapy
- Abstract
Despite the advent of novel therapies which manage and control diabetes well, the increased risk of morbidity and mortality in diabetic subjects is associated with the devastating secondary complications it produces. Long-standing diabetes majorly drives cellular and molecular alterations, which eventually damage both small and large blood vessels. The complications are prevalent both in type I and type II diabetic subjects. The microvascular complications include diabetic neuropathy, diabetic nephropathy, diabetic retinopathy, while the macrovascular complications include diabetic heart disease and stroke. The current therapeutic strategy alleviates the complications to some extent but does not cure or prevent them. Also, the recent clinical trial outcomes in this field are disappointing. Success in the drug discovery of diabetic complications may be achieved by a better understanding of the underlying pathophysiology and by recognising the crucial factors contributing to the development and progression of the disease. In this review, we discuss the well-studied cellular mechanisms leading to the development and progression of diabetic complications. In addition, we also highlight the various therapeutic paradigms currently in clinical practice., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.net.)
- Published
- 2022
- Full Text
- View/download PDF
34. Cellular experiments to study the inhibition of c-Myc/MAX heterodimerization.
- Author
-
Singh A, Sharma S, Kumar P, and Garg N
- Subjects
- Basic Helix-Loop-Helix Leucine Zipper Transcription Factors genetics, DNA metabolism, Dimerization, Gene Expression Regulation, Proto-Oncogene Proteins c-myc chemistry, Proto-Oncogene Proteins c-myc genetics, Proto-Oncogene Proteins c-myc metabolism, Transcription Factors genetics
- Abstract
The c-Myc oncogene is a master regulator of cancer cell metabolism, which controls a variety of pathways, including cell proliferation, cell cycle, apoptosis, and epigenetics. Belonging to the bHLH family of transcription factors, c-Myc forms a heterodimeric complex with another bHLH family protein MAX. c-Myc deregulation is reported in most cancers. This heterodimeric complex is a potent transcription factor that controls the expression of the target gene by binding to the E-box sequence and thereby controlling cancer cell proliferation. c-Myc in isolation has a partially folded structure and cannot carry the transcription. However, its heterodimerization provides the ability to bind DNA and carry out the regulatory function. Therefore, heterodimerization of c-Myc and Max is of great interest for cancers, and it has always been considered a target for cancer therapy. This book chapter will present a detailed protocol of cellular experiments employed to validate the in vitro potency of c-Myc inhibitor candidates to search for a novel c-Myc-targeted neoplastic drug., (Copyright © 2022 Elsevier Inc. All rights reserved.)
- Published
- 2022
- Full Text
- View/download PDF
35. G-Protein-Coupled Receptor (GPCR) Signaling in the Carotid Body: Roles in Hypoxia and Cardiovascular and Respiratory Disease.
- Author
-
Aldossary, Hayyaf S., Alzahrani, Abdulaziz A., Nathanael, Demitris, Alhuthail, Eyas A., Ray, Clare J., Batis, Nikolaos, Kumar, Prem, Coney, Andrew M., and Holmes, Andrew P.
- Subjects
- *
CAROTID body , *RESPIRATORY diseases , *CARDIOVASCULAR diseases , *OXYGEN in the blood , *HYPOXEMIA - Abstract
The carotid body (CB) is an important organ located at the carotid bifurcation that constantly monitors the blood supplying the brain. During hypoxia, the CB immediately triggers an alarm in the form of nerve impulses sent to the brain. This activates protective reflexes including hyperventilation, tachycardia and vasoconstriction, to ensure blood and oxygen delivery to the brain and vital organs. However, in certain conditions, including obstructive sleep apnea, heart failure and essential/spontaneous hypertension, the CB becomes hyperactive, promoting neurogenic hypertension and arrhythmia. G-protein-coupled receptors (GPCRs) are very highly expressed in the CB and have key roles in mediating baseline CB activity and hypoxic sensitivity. Here, we provide a brief overview of the numerous GPCRs that are expressed in the CB, their mechanism of action and downstream effects. Furthermore, we will address how these GPCRs and signaling pathways may contribute to CB hyperactivity and cardiovascular and respiratory disease. GPCRs are a major target for drug discovery development. This information highlights specific GPCRs that could be targeted by novel or existing drugs to enable more personalized treatment of CB-mediated cardiovascular and respiratory disease. [ABSTRACT FROM AUTHOR]
- Published
- 2020
- Full Text
- View/download PDF
36. Exploring the newer oxadiazoles as real inhibitors of human SIRT2 in hepatocellular cancer cells.
- Author
-
Dukanya, Shanmugam, Muthu K., Rangappa, Shobith, Metri, Prashant K., Mohan, Surender, Basappa, and Rangappa, Kanchugarakoppal S.
- Abstract
A novel series of indazole tethered oxadiazoles (OTDs) derivatives were synthesized, characterized and screened for their anti-proliferative activity against hepatocellular carcinoma (HCC) cells. OTDs structure was further confirmed by Single-crystal X-ray diffraction studies. Among the tested OTDs, compound 2-(4-methoxyphenyl)-5-(1-methyl-1H-indazol-3-yl)-1,3,4-oxadiazole was found to inhibit the catalytical activity of SIRT2 and brings about apoptosis as shown by western blot analysis and flow cytometry data. Also, the tested OTDs were found to interact with the active site of human SIRT2 in silico but not with the cavity of co-crystal ligand 5-(3- hydroxypropyl)-3-(4-chlorophenyl)-1,2,4-oxadiazole, which indicate that these OTDs has potential in the development of SIRT2 inhibitors in liver cancer models. [ABSTRACT FROM AUTHOR]
- Published
- 2020
- Full Text
- View/download PDF
37. Discovery of novel inhibitors to investigate diacylglycerol lipases and α/β hydrolase domain 16A
- Author
-
Janssen, F.J., Overkleeft, H.S., Stelt, M. van der, Maccarrone, M., Boeckel, C.A.A. van, Hirsch, A.K.H., Brouwer, J., Kasteren, S. van, and Leiden University
- Subjects
Neuroinflammation ,Drug-discovery ,Serine-hydrolases ,A/b-hydrolase domain16A ,PHARC ,Medicinal-chemistry ,Obesity ,Diacylglycerol-lipases ,Endocannabinoids - Abstract
This Thesis reports on the discovery and optimization of potent inhibitors for the serine hydrolases sn-1 diacylglycerol lipase α (DAGLα) and α/β hydrolase domain 16A (ABHD16A). Several structure- and ligand-based drug discovery methodologies were employed, such as in silico screening and high throughput screening, in combination with activity-based protein profiling (ABPP). The glycine sulfonamides reported in this Thesis, such as LEI106, are important peripherally restricted inhibitors that can be used to evaluate the contribution of perturbing DAGL activity in the potential treatment of metabolic syndrome, diabetes and pheriphiral obesity. The α-keto heterocycles in this Thesis, such as LEI107, could be important inhibitors to evaluate if a therapeutic window can be established for (central) DAGL inhibitors in the potential treatment of addiction, obesity and neuroinflammation. Lastly, 1,2,4-triazole urea sulfonamides that are reported in this Thesis can be used as novel tool compounds to evaluate DAGL and ABHD16A function in both health and disease.
- Published
- 2016
38. Plate-based diversity subset screening generation 2: an improved paradigm for high-throughput screening of large compound files
- Author
-
James Edward John Mills, Robert E. Sharp, Joe Bradley, Jens Loesel, Marie-Claire Peakman, Christine Williams, David McLoughlin, Jeremy R. Everett, Hongyao Zhu, and Andrew Simon Bell
- Subjects
0301 basic medicine ,SELECTION ,Selection (relational algebra) ,Computer science ,Chemistry, Multidisciplinary ,Drug Evaluation, Preclinical ,Chemistry, Medicinal ,computer.software_genre ,2nd Generation ,High-throughput screening (HTS) ,Screening file ,DESIGN ,Drug Discovery ,QD ,Pharmacology & Pharmacy ,Ro40 ,Lead discovery ,OF-THE-ART ,Diversity ,PRODUCTIVITY ,Drug discovery ,RESEARCH-AND-DEVELOPMENT ,Rule of 40 ,General Medicine ,CHEMICAL DIVERSITY ,Chemistry, Applied ,Chemistry ,Physical Sciences ,Original Article ,Data mining ,Life Sciences & Biomedicine ,Algorithms ,Information Systems ,Biochemistry & Molecular Biology ,EFFICIENCY ,High-throughput screening ,DRUG-DISCOVERY ,Nanotechnology ,Catalysis ,Inorganic Chemistry ,Small Molecule Libraries ,03 medical and health sciences ,Subset ,High-Throughput Screening Assays ,Computer Simulation ,Physical and Theoretical Chemistry ,Molecular Biology ,Plate-based ,Science & Technology ,Organic Chemistry ,Reproducibility of Results ,IN-VITRO ,Chemical space ,030104 developmental biology ,Biological target ,Chemical diversity ,computer - Abstract
High-throughput screening (HTS) is an effective method for lead and probe discovery that is widely used in industry and academia to identify novel chemical matter and to initiate the drug discovery process. However, HTS can be time consuming and costly and the use of subsets as an efficient alternative to screening entire compound collections has been investigated. Subsets may be selected on the basis of chemical diversity, molecular properties, biological activity diversity or biological target focus. Previously, we described a novel form of subset screening: plate-based diversity subset (PBDS) screening, in which the screening subset is constructed by plate selection (rather than individual compound cherry-picking), using algorithms that select for compound quality and chemical diversity on a plate basis. In this paper, we describe a second-generation approach to the construction of an updated subset: PBDS2, using both plate and individual compound selection, that has an improved coverage of the chemical space of the screening file, whilst only selecting the same number of plates for screening. We describe the validation of PBDS2 and its successful use in hit and lead discovery. PBDS2 screening became the default mode of singleton (one compound per well) HTS for lead discovery in Pfizer. Electronic supplementary material The online version of this article (doi:10.1007/s11030-016-9692-9) contains supplementary material, which is available to authorized users.
- Published
- 2016
39. Novel Strategies for Drug Discovery Based on Intrinsically Disordered Proteins (IDPs)
- Author
-
Liling Zhao, Zanxia Cao, Shuqiang Li, and Jihua Wang
- Subjects
Review ,Computational biology ,Biology ,Intrinsically disordered proteins ,Catalysis ,Inorganic Chemistry ,Sequence Analysis, Protein ,Interaction network ,Drug Discovery ,Amino Acid Sequence ,Protein Interaction Maps ,Physical and Theoretical Chemistry ,Molecular Biology ,Spectroscopy ,structural characterizations ,Genetics ,Drug discovery ,interaction networks ,Organic Chemistry ,sequence characterizations ,General Medicine ,Protein Structure, Tertiary ,Computer Science Applications ,Intrinsically Disordered Proteins ,Many to one ,drug-discovery ,Protein network ,Protein p53 ,Protein Interaction Map - Abstract
Intrinsically disordered proteins (IDPs) are proteins that usually do not adopt well-defined native structures when isolated in solution under physiological conditions. Numerous IDPs have close relationships with human diseases such as tumor, Parkinson disease, Alzheimer disease, diabetes, and so on. These disease-associated IDPs commonly play principal roles in the disease-associated protein-protein interaction networks. Most of them in the disease datasets have more interactants and hence the size of the disease-associated IDPs interaction network is simultaneously increased. For example, the tumor suppressor protein p53 is an intrinsically disordered protein and also a hub protein in the p53 interaction network; α-synuclein, an intrinsically disordered protein involved in Parkinson diseases, is also a hub of the protein network. The disease-associated IDPs may provide potential targets for drugs modulating protein-protein interaction networks. Therefore, novel strategies for drug discovery based on IDPs are in the ascendant. It is dependent on the features of IDPs to develop the novel strategies. It is found out that IDPs have unique structural features such as high flexibility and random coil-like conformations which enable them to participate in both the “one to many” and “many to one” interaction. Accordingly, in order to promote novel strategies for drug discovery, it is essential that more and more features of IDPs are revealed by experimental and computing methods.
- Published
- 2011
- Full Text
- View/download PDF
40. Selective inhibitors of trypanosomal uridylyl transferase RET1 establish druggability of RNA post-transcriptional modifications
- Author
-
Eric A. Miska, Beth Thomas, Michael V. Gormally, Peter J. Bond, Amy C. Cording, Mark Carrington, Shankar Balasubramanian, Carrington, Mark [0000-0002-6435-7266], Balasubramanian, Shankar [0000-0002-0281-5815], Miska, Eric [0000-0002-4450-576X], and Apollo - University of Cambridge Repository
- Subjects
0301 basic medicine ,RNA, Untranslated ,Trypanosoma brucei brucei ,non-coding RNA ,Protozoan Proteins ,Druggability ,Uridine Triphosphate ,Computational biology ,Biology ,Trypanosoma brucei ,03 medical and health sciences ,RNA modifications ,trypanosome ,uridylylation ,Drug Discovery ,Sense (molecular biology) ,Humans ,African trypanosomiasis ,Molecular Biology ,post-transcriptional modification ,Nucleic Acid Synthesis Inhibitors ,RET1 ,Drug discovery ,RNA ,RNA Nucleotidyltransferases ,TUTase ,Cell Biology ,Non-coding RNA ,biology.organism_classification ,Trypanocidal Agents ,Virology ,Post-transcriptional modification ,Trypanosomiasis, African ,030104 developmental biology ,RNA editing ,RNA Editing ,drug-discovery ,Research Paper - Abstract
Non-coding RNAs are crucial regulators for a vast array of cellular processes and have been implicated in human disease. These biological processes represent a hitherto untapped resource in our fight against disease. In this work we identify small molecule inhibitors of a non-coding RNA uridylylation pathway. The TUTase family of enzymes is important for modulating non-coding RNA pathways in both human cancer and pathogen systems. We demonstrate that this new class of drug target can be accessed with traditional drug discovery techniques. Using the Trypanosoma brucei TUTase, RET1, we identify TUTase inhibitors and lay the groundwork for the use of this new target class as a therapeutic opportunity for the under-served disease area of African Trypanosomiasis. In a broader sense this work demonstrates the therapeutic potential for targeting RNA post-transcriptional modifications with small molecules in human disease.
- Published
- 2016
- Full Text
- View/download PDF
41. Metabolomics-Driven Exploration of the Chemical Drug Space to Predict Combination Antimicrobial Therapies.
- Author
-
Campos, Adrian I. and Zampieri, Mattia
- Subjects
- *
PHARMACOGENOMICS , *DRUG side effects , *DRUG design , *DRUG tolerance , *METABOLIC profile tests , *DRUG interactions - Abstract
Alternative to the conventional search for single-target, single-compound treatments, combination therapies can open entirely new opportunities to fight antibiotic resistance. However, combinatorial complexity prohibits experimental testing of drug combinations on a large scale, and methods to rationally design combination therapies are lagging behind. Here, we developed a combined experimental-computational approach to predict drug-drug interactions using high-throughput metabolomics. The approach was tested on 1,279 pharmacologically diverse drugs applied to the gram-negative bacterium Escherichia coli. Combining our metabolic profiling of drug response with previously generated metabolic and chemogenomic profiles of 3,807 single-gene deletion strains revealed an unexpectedly large space of inhibited gene functions and enabled rational design of drug combinations. This approach is applicable to other therapeutic areas and can unveil unprecedented insights into drug tolerance, side effects, and repurposing. The compendium of drug-associated metabolome profiles is available at https://zampierigroup.shinyapps.io/EcoPrestMet , providing a valuable resource for the microbiological and pharmacological communities. • Metabolic profiling of E. coli response to 1,279 chemically diverse drugs • Large space of nonessential gene functions affected by human-targeted drugs • Genome-scale inference of drug targets and indirect mediators of drug response • Metabolome and chemogenomic profiling predict epistatic interactions between drugs Campos and Zampieri monitor the metabolic response of E. coli to 1,279 drugs and reveal an unexpectedly large spectrum of metabolic effects. Combining metabolic profiling with chemogenomic data, they predict epistatic drug interactions and show how to expand the search for new antimicrobial treatments to compounds with no growth-inhibitory activity. [ABSTRACT FROM AUTHOR]
- Published
- 2019
- Full Text
- View/download PDF
42. Repurposing FDA approved drugs against the human fungal pathogen, Candida albicans
- Author
-
Leeor Zilbermintz, Kevin Kim, and Mikhail Martchenko
- Subjects
Microbiology (medical) ,medicine.medical_specialty ,Antifungal Agents ,Off-label drug use ,Drug resistance ,Microbial Sensitivity Tests ,Off-label use ,Antifungal ,Microbiology ,Medical microbiology ,Drug-discovery ,Candida albicans ,medicine ,Microbial Viability ,biology ,Drug discovery ,Research ,Small molecules ,Drug Repositioning ,General Medicine ,biology.organism_classification ,Corpus albicans ,Drug repositioning ,Infectious Diseases ,Parasitology - Abstract
Background The high cost and prolonged timeline of new drug discovery and development are major roadblocks to creating therapies for infectious diseases. Candida albicans is an opportunistic fungal pathogen that is the most common cause of fatal fungal infections in humans and costs $2–4 billion dollars to treat in the US alone. Methods To accelerate drug discovery, we screened a library of 1581 existing FDA approved drugs, as well as drugs approved abroad, for inhibitors of C. albicans. The screen was done on YPD yeast growth media as well as on the serum plate assay developed in this study. Results We discovered that fifteen drugs, all which were originally approved for treating various infectious and non-infectious diseases, were able to kill Candida albicans. Additionally, one of those drugs, Octodrine, displays wide-spectrum anti-microbial activity. Compared to other selected anti-Candida drugs, Octodrine was shown to be one of the most effective drugs in killing serum-grown Candida albicans without significantly affecting the survival of host macrophages and skin cells. Conclusions This approach is useful for the discovery of economically viable new therapies against infectious diseases. Electronic supplementary material The online version of this article (doi:10.1186/s12941-015-0090-4) contains supplementary material, which is available to authorized users.
- Published
- 2015
43. 2D and 3D similarity landscape analysis identifies PARP as a novel off-target for the drug Vatalanib
- Author
-
Bjoern-Oliver Gohlke, Robert Preissner, Anja Richter, Antje Richter, Tim Overkamp, Bernd Gillissen, and Peter T. Daniel
- Subjects
FOS: Computer and information sciences ,Vascular Endothelial Growth Factor A ,Cancer Research ,Vatalanib ,Pyridines ,Structural similarity ,medicine.drug_class ,Bioinformatics ,Computational biology ,Poly(ADP-ribose) Polymerase Inhibitors ,Biology ,600 Technik, Medizin, angewandte Wissenschaften::610 Medizin und Gesundheit ,Polyadenylation ,Biochemistry ,Poly (ADP-Ribose) Polymerase Inhibitor ,PARP ,Similarity (network science) ,Structural Biology ,Drug-discovery ,medicine ,Humans ,Mode of action ,Molecular Biology ,Genetics ,Binding Sites ,Drug discovery ,Applied Mathematics ,Computational Biology ,Vascular endothelial growth factor (VEGF) ,Protein kinase inhibitor ,Drug action ,Protein Structure, Tertiary ,Computer Science Applications ,Molecular Docking Simulation ,Microscopy, Fluorescence ,PARP inhibitor ,MCF-7 Cells ,Phthalazines ,Colorimetry ,Poly(ADP-ribose) Polymerases ,Research Article ,Protein Binding ,3D similarity landscapes - Abstract
Background Searching for two-dimensional (2D) structural similarities is a useful tool to identify new active compounds in drug-discovery programs. However, as 2D similarity measures neglect important structural and functional features, similarity by 2D might be underestimated. In the present study, we used combined 2D and three-dimensional (3D) similarity comparisons to reveal possible new functions and/or side-effects of known bioactive compounds. Results We utilised more than 10,000 compounds from the SuperTarget database with known inhibition values for twelve different anti-cancer targets. We performed all-against-all comparisons resulting in 2D similarity landscapes. Among the regions with low 2D similarity scores are inhibitors of vascular endothelial growth factor receptor (VEGFR) and inhibitors of poly ADP-ribose polymerase (PARP). To demonstrate that 3D landscape comparison can identify similarities, which are untraceable in 2D similarity comparisons, we analysed this region in more detail. This 3D analysis showed the unexpected structural similarity between inhibitors of VEGFR and inhibitors of PARP. Among the VEGFR inhibitors that show similarities to PARP inhibitors was Vatalanib, an oral “multi-targeted” small molecule protein kinase inhibitor being studied in phase-III clinical trials in cancer therapy. An in silico docking simulation and an in vitro HT universal colorimetric PARP assay confirmed that the VEGFR inhibitor Vatalanib exhibits off-target activity as a PARP inhibitor, broadening its mode of action. Conclusion In contrast to the 2D-similarity search, the 3D-similarity landscape comparison identifies new functions and side effects of the known VEGFR inhibitor Vatalanib. Electronic supplementary material The online version of this article (doi:10.1186/s12859-015-0730-x) contains supplementary material, which is available to authorized users.
- Published
- 2015
44. Text mining for drug discovery
- Author
-
Piliouras, Dimitrios and Ananiadou, Sophia
- Subjects
drug-NER ,text-mining ,pharmacology ,drug-discovery - Abstract
Over the last several decades, medical and biological research has risen to extraor-dinary levels, opening vast windows into the mechanisms underlying health and dis-ease in living organisms. Integrating this knowledge into a unified framework to en-hance our understanding and decision-making is a significant challenge for the researchcommunity. Efficient drug discovery and development requires methods for bridgingpre-clinical data with patient data, as well as effective literature-mining, in order to es-timate both efficacy and safety outcomes for new molecules and treatment approaches.Text mining is often regarded as an antidote to this exponential growth of biomedicalpublications.In this thesis text-mining and natural-language-processing techniques and tools,aiming to assist with various computational aspects of drug-discovery, are presented.In particular, methods useful for modelling of pharmaco-kinetic parameters, a processby which, the pharmaceutical effects of a drug can be simulated using mathematicalmodels, are pursued. In order to fully realise the potential of such modelling, there isa tremendous need for databases of verified pharmaco-kinetic/dynamic properties ofdrugs. To that end, a context-free-grammar, capable of capturing such parameters, andtheir potential modifications, is proposed. The fully deterministic nature of a contextfree grammar can be side-stepped by embedding a lexical analyser which is able toplug-in external components for specialised sub-tasks (i.e., named entity recognition).The feasibility of this approach is evaluated against a gold-standard corpus, where it isshown to be both effective and efficient, with predictive accuracy touching 90%.
- Published
- 2014
45. Synthesis of small molecule inhibitors for the treatment of disease
- Author
-
Stocker, Bridget, Timmer, Mattie, Corkran, Hilary Mary, Stocker, Bridget, Timmer, Mattie, and Corkran, Hilary Mary
- Abstract
Three aspects of the protecting-group-free (PGF) synthesis of small molecules have been described in this thesis. In the first part, the PGF azasugar synthesis methodology was applied to 2-deoxy-D-glucose with the intention of selectively forming the six-membered azasugar 5-epi-fagomine. Surprisingly, four products were formed in the key I2-mediated carbamate annulation step, with a pyrrolidine being the major product after optimisation. This was formed in 15% yield. A mechanism that explains the formation of the four carbamates was proposed, which was supported by an investigation into related halocyclisation reactions. The next part of this thesis describes the development of a new PGF methodology for the synthesis of conduramines, another class of biologically interesting molecules. Conduramines are amino polyhydroxy cyclohexenes and some conduramines have glycosidase inhibitory activity. These molecules are also useful precursors to a variety of biologically useful molecules including aminocyclitols and azasugars. The key steps in the PGF synthesis of conduramines are a Vasella-Barbier amination, a reaction that forms new C-C and C-N bonds concomitantly, and a ring closing metathesis in the presence of free hydroxyl and amine groups. To this end, a 4-deoxy 3-conduramine was prepared in just four steps and in 27% yield. Finally, the preparation of an amine library and its biological testing for the identification of a new anti-tuberculosis drug is described. Two short syntheses were used to prepare alkenylamines and amines from the corresponding sugar, with various lipophilic groups attached to the amine. A 20-member amine library was prepared, and the compounds were tested for anti-mycobacterial activity in a mycobacterial growth inhibition assay. The most active compounds were subjected to further biological testing to determine their general cytotoxic properties. Two amines, arabinohexadecylamine and arabinohexadecylmethylamine, were identified as having the b
- Published
- 2014
46. WISDOM
- Author
-
Salzemann, J., Bloch, V., Laboratoire de Physique Corpusculaire - Clermont-Ferrand (LPC), Université Blaise Pascal - Clermont-Ferrand 2 (UBP)-Institut National de Physique Nucléaire et de Physique des Particules du CNRS (IN2P3)-Centre National de la Recherche Scientifique (CNRS), and WISDOM
- Subjects
bioinformatics ,[INFO.INFO-DC]Computer Science [cs]/Distributed, Parallel, and Cluster Computing [cs.DC] ,[INFO.INFO-BI]Computer Science [cs]/Bioinformatics [q-bio.QM] ,drug-discovery ,large scale deployment - Abstract
Demo, Abstracts Book; The environment evolved throughout the development: It was first made of a set ofscripts that generate the jobs, submit the files and check regularly their statuswhile they are on the Grid. Through this abstract we want to present the newenvironement that is based on the AMGA metadata catalog for more flexibility andon a Java environment that can be used through web services. The environment isvery flexible and can be used for any type of bioinformatics application.In thisnew environment we control the job distribution, maintaing the choice of directlysubmitting the executable (push mode) or implementing a two-way submission wherethe system submits generic wrapper jobs which request their paylod (theexecutable and the input data) only when they start to be executed (pull mode).
- Published
- 2008
47. The In Silico Drug Discovery Toolbox: Applications in Lead Discovery and Optimization.
- Author
-
Bruno A, Costantino G, Sartori L, and Radi M
- Subjects
- Humans, Machine Learning, Pharmaceutical Preparations chemistry, Computer-Aided Design, Drug Design, Drug Discovery, Pharmaceutical Preparations chemical synthesis
- Abstract
Background: Discovery and development of a new drug is a long lasting and expensive journey that takes around 20 years from starting idea to approval and marketing of new medication. Despite R&D expenditures have been constantly increasing in the last few years, the number of new drugs introduced into market has been steadily declining. This is mainly due to preclinical and clinical safety issues, which still represent about 40% of drug discontinuation. To cope with this issue, a number of in silico techniques are currently being used for an early stage evaluation/prediction of potential safety issues, allowing to increase the drug-discovery success rate and reduce costs associated with the development of a new drug., Methods: In the present review, we will analyse the early steps of the drug-discovery pipeline, describing the sequence of steps from disease selection to lead optimization and focusing on the most common in silico tools used to assess attrition risks and build a mitigation plan., Results: A comprehensive list of widely used in silico tools, databases, and public initiatives that can be effectively implemented and used in the drug discovery pipeline has been provided. A few examples of how these tools can be problem-solving and how they may increase the success rate of a drug discovery and development program have been also provided. Finally, selected examples where the application of in silico tools had effectively contributed to the development of marketed drugs or clinical candidates will be given., Conclusion: The in silico toolbox finds great application in every step of early drug discovery: (i) target identification and validation; (ii) hit identification; (iii) hit-to-lead; and (iv) lead optimization. Each of these steps has been described in details, providing a useful overview on the role played by in silico tools in the decision-making process to speed-up the discovery of new drugs., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.net.)
- Published
- 2019
- Full Text
- View/download PDF
48. Effect of combining in vitro estrogenicity data with kinetic characteristics of estrogenic compounds on the in vivo predictive value
- Author
-
Punt, A., Brand, W., Murk, A.J., van Wezel, Annemarie, Schriks, M., Heringa, M.B., Environmental Sciences, and Environmental Sciences
- Subjects
binding ,Bisphenol ,Genistein ,Pharmacology ,Toxicology ,Ethinyl Estradiol ,Endocrine disruptive compounds ,oecd program ,chemistry.chemical_compound ,rat uterotrophic bioassay ,ADME ,Chemistry ,er-alpha ,In vitro toxicology ,General Medicine ,Organ Size ,Liver ,human-liver-microsomes ,Microsomes, Liver ,Biological Assay ,Female ,Hepatic clearance ,drug-discovery ,receptor-alpha ,antiestrogenic activity ,physicochemical properties ,Phenols ,In vivo ,Estrogenic effect ,Cell Line, Tumor ,Animals ,Humans ,Benzhydryl Compounds ,Toxicologie ,WIMEK ,In vitro bioassays ,Uterus ,Estrogen Receptor alpha ,Reproducibility of Results ,Estrogens ,Equivalence factors ,In vitro ,Bioavailability ,Rats ,Kinetics ,bisphenol-a ,Metabolism ,Estrogen receptor alpha - Abstract
With the ultimate aim of increasing the utility of in vitro assays for toxicological risk assessment, a method was developed to calculate in vivo estrogenic potencies from in vitro estrogenic potencies of compounds by taking into account systemic availability. In vitro estrogenic potencies of three model compounds (bisphenol A, genistein, and 4-nonylphenol) relative to ethinylestradiol (EE2), determined with the estrogen receptor alpha (ERα) transcriptional activation assay using hER-HeLa-9903 cells, were taken from literature and used to calculate the EE2 equivalent (EE2EQ) effect doses in the predominantly ERα-dependent rat uterotrophic assay. Compound-specific differences in hepatic clearance relative to the reference compound EE2 were determined in vitro to examine whether in vivo estrogenic potencies reported in literature could be more accurately estimated. The EE2EQ doses allowed to predict in vivo uterotrophic responses within a factor of 6-25 and the inclusion of the hepatic clearance further improved the prediction with a factor 1.6-2.1 for especially genistein and bisphenol A. Yet, the model compounds still were less potent in vivo than predicted based on their EE2 equivalent estrogenic potency and hepatic clearance. For further improvement of the in vitro to in vivo predictive value of in vitro assays, the relevance of other kinetic characteristics should be studied, including binding to carrier proteins, oral bioavailability and the formation of estrogenic metabolites.
- Published
- 2013
49. EXPLORATION OF THE SRX-PRX AXIS AS A SMALL-MOLECULE TARGET
- Author
-
Mishra, Murli
- Subjects
- Sulfiredoxin, Peroxiredoxin, Drug-discovery, Lung cancer, Carcinogenesis, Metastasis inhibitor, Bioinformatics, Medicinal and Pharmaceutical Chemistry, Medicinal Chemistry and Pharmaceutics, Pharmaceutics and Drug Design, Pharmacology, Toxicology
- Abstract
Lung cancer is a leading cause of cancer-related mortality irrespective of gender. The Sulfiredoxin (Srx) and Peroxiredoxin (Prx) are a group of thiol-based antioxidant proteins that plays an essential role in non-small cell lung cancer. Understanding the molecular characteristics of the Srx-Prx interaction may help design the strategies for future development of therapeutic tools. Based on existing literature and preliminary data from our lab, we hypothesized that the Srx plays a critical role in lung carcinogenesis and targeting the Srx-Prx axis or Srx alone may facilitate future development of targeted therapeutics for prevention and treatment of lung cancer. First, we demonstrated the oncogenic role of Srx in urethane-induced lung carcinogenesis in genetically modified FVB mice. The Srx-null mice showed resistance to urethane-induced lung cancer. Second, we demonstrated the Srx and Prx sites important for Srx-Prx interaction. The orientation of this arm is demonstrated to cause some steric hindrance for the Srx-Prx interaction as it substantially reduces the rate of association between Srx and Prx. Finally, we carried out virtual screening to identify molecules that can successfully target Srx-Prx interaction. Multiple in-silico filters were used to minimize the number of chemicals to be tested. We identified ISO1 as an inhibitor of the Srx-Prx interaction. KD value for Srx-ISO1 interaction is calculated to be 42 nM. Together, these data helps to identify an inhibitor (ISO1) of the Srx-Prx interaction that can be further pursued to be developed as a chemotherapeutic tool.
- Published
- 2016
50. Gymnema sylvestre for Diabetes: From Traditional Herb to Future's Therapeutic.
- Author
-
Tiwari P, Ahmad K, and Baig MH
- Subjects
- Animals, Biological Products chemistry, Biological Products isolation & purification, Humans, Hypoglycemic Agents chemistry, Hypoglycemic Agents isolation & purification, Molecular Conformation, Plant Extracts chemistry, Plant Extracts isolation & purification, Biological Products therapeutic use, Diabetes Mellitus drug therapy, Gymnema sylvestre chemistry, Hypoglycemic Agents therapeutic use, Plant Extracts therapeutic use
- Abstract
Diabetes has increased at an unprecedented rate and is fast emerging as a global threat worldwide. The focus on pharmacological studies pertaining to diabetes has seen a remarkable shift from conventional medicines to therapeutics employing bioactive phytomolecules from natural sources. The prospective effectiveness of natural products together with their low cost and minimal side effects has revolutionized the entire concept of drug discovery and management programs. One such beneficial herb is Gymnema sylvestre, possessing remarkable hypoglycemic properties and forms the platform of diabetes therapeutics in the traditional system of medication. The present article discusses the significance of G. sylvestre in diabetes management, the herbal-formulations from the herb together with its standardization and clinical trials on animal models, and why Peroxisome Proliferator Activated Receptor gamma (PPARγ) may serve as a prospective molecular target for Gymnemic acid analogs. Such studies would define the molecular basis of bioactive molecules which would aid in the development of natural product based therapeutics in the treatment of diabetes., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.org.)
- Published
- 2017
- Full Text
- View/download PDF
Catalog
Discovery Service for Jio Institute Digital Library
For full access to our library's resources, please sign in.