20,686 results on '"INHIBITORS"'
Search Results
2. Artemisia campestris L. as a promising source of potential antiviral drugs for SARS-CoV-2: Docking and dynamic simulation studies
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Khelef, Aboubakeur Esseddik, Hadni, Hanine, Gouzi, Hicham, and Grama, Borhane Samir
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- 2024
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Catalog
3. Unexpected inhibition roles of methane nanobubbles on hydrate decomposition
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Guo, Muzhi, Li, Wenkai, Yin, Qi, Wu, Wenbing, Wang, Xiansi, Yan, Youguo, Zhang, Jun, and Zhong, Jie
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- 2024
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4. Nonneutralizing antibodies in Nordic persons with moderate hemophilia A and B (the MoHem study)
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Måseide, Ragnhild J., Berntorp, Erik, Astermark, Jan, Olsson, Anna, Bruzelius, Maria, Frisk, Tony, Nummi, Vuokko, Lassila, Riitta, Strandberg, Karin, Tjønnfjord, Geir E., and Holme, Pål A.
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- 2024
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5. Biohydrogen fermentation from pretreated biomass in lignocellulose biorefinery: Effects of inhibitory byproducts and recent progress in mitigation strategies
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Zhao, Zi-Tong, Yang, Shan-Shan, Luo, Geng, Sun, Han-Jun, Liu, Bing-Feng, Cao, Guang-Li, Bao, Mei-Yi, Pang, Ji-Wei, Ren, Nan-Qi, and Ding, Jie
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- 2025
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6. Targeting ferroptosis offers therapy choice in sepsis-associated acute lung injury
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Wang, Yu, Wang, Weixue, Zhang, Yi, Fleishman, Joshua S., and Wang, Hongquan
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- 2025
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7. Discovery of novel biaryl urea derivatives against IL-1β release with low toxicity based on NEK7 inhibitor
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Wang, Leibo, Zhu, Kehan, Tian, Ziyang, Wang, Haoyu, Jia, Yulei, Feng, Chunlan, Qi, Luyao, Tang, Wei, and Hu, Youhong
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- 2025
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8. Discovery, synthesis, and antibacterial activity of novel myrtucommulone analogs as inhibitors of DNA gyrase and topoisomerase IV
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Yang, Hao, Li, Jian, Wang, Bo-Lin, Yang, Xin-Ya, and Zhang, Yu
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- 2025
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9. Discovery of acetohydroxyacid synthase inhibitors as anti-tuberculosis lead compounds from natural products
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Niu, Yanhong, Wu, Zhili, Hu, Qianfang, Wu, Yuchen, Jiang, Qihua, and Yang, Xiaolan
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- 2025
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10. PAK2 as a therapeutic target in cancer: Mechanisms, challenges, and future perspectives
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Chen, Xin-Pan, Yang, Zi-Tao, Yang, Shang-Xin, Li, En-Min, and Xie, Lei
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- 2025
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11. Identification of potential dipeptidyl peptidase IV inhibitors from the ConMedNP library by virtual screening, and molecular dynamics methods
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Tsahnang Fofack, Hans Merlin, Mbah Bake, Maraf, Petry, Simon, Ateba, Baruch A., Amoa Onguéné, Pascal, Mohammad-Salim, Haydar, Ntie-Kang, Fidele, Mbaze, Luc Meva'a, Vakal, Serhii, and Kenfack, Cyril A
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- 2024
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12. A second life for MAO inhibitors? From CNS diseases to anticancer therapy
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Sblano, Sabina, Boccarelli, Angelina, Mesiti, Francesco, Purgatorio, Rosa, de Candia, Modesto, Catto, Marco, and Altomare, Cosimo D.
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- 2024
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13. Nano-based surface adsorption detoxification of process inhibitors for improved bioethanol productivity
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Adebule, Adeniyi P., Sanusi, Isaac A., and Kana, E.B. Gueguim
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- 2024
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14. The Survey of Barriers for Vaginal Access Surgery Study
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Halder, Gabriela E., Ferrando, Cecile A., Rogers, Rebecca, Elhenawy, Caren, Grimes, Cara L., Balgobin, Sunil, Kho, Rosanne M., and Sokol, Andrew I.
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- 2024
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15. A novel automated chemiluminescent enzyme immunoassay for ADAMTS-13 activity enables accompanying measurements of the inhibitory autoantibodies
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Kubo, Masayuki, Konko, Kazuyasu, Kinoshita, Emi, Uemae, Satoshi, Kobayashi, Katsushi, Hayashi, Yoshinori, Kan, Akihiko, Fujimura, Yoshihiro, and Matsumoto, Masanori
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- 2024
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16. Allosteric regulation of the inactive to active state conformational transition in CDPK1 protein of Plasmodium falciparum
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Gupta, Priya and Mohanty, Debasisa
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- 2022
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17. Structure-based discovery of CFTR potentiators and inhibitors.
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Liu, Fangyu, Kaplan, Anat, Levring, Jesper, Einsiedel, Jürgen, Tiedt, Stephanie, Distler, Katharina, Omattage, Natalie, Kondratov, Ivan, Moroz, Yurii, Pietz, Harlan, Irwin, John, Gmeiner, Peter, Shoichet, Brian, and Chen, Jue more...
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ABC transporter ,anion channel ,inhibitors ,large-scale docking ,ligand discovery ,potentiators ,Cystic Fibrosis Transmembrane Conductance Regulator ,Humans ,Molecular Docking Simulation ,Cystic Fibrosis ,Aminophenols ,Drug Discovery ,Cryoelectron Microscopy ,Quinolones ,Allosteric Site ,Animals ,Ligands - Abstract
The cystic fibrosis transmembrane conductance regulator (CFTR) is a crucial ion channel whose loss of function leads to cystic fibrosis, whereas its hyperactivation leads to secretory diarrhea. Small molecules that improve CFTR folding (correctors) or function (potentiators) are clinically available. However, the only potentiator, ivacaftor, has suboptimal pharmacokinetics and inhibitors have yet to be clinically developed. Here, we combine molecular docking, electrophysiology, cryo-EM, and medicinal chemistry to identify CFTR modulators. We docked ∼155 million molecules into the potentiator site on CFTR, synthesized 53 test ligands, and used structure-based optimization to identify candidate modulators. This approach uncovered mid-nanomolar potentiators, as well as inhibitors, that bind to the same allosteric site. These molecules represent potential leads for the development of more effective drugs for cystic fibrosis and secretory diarrhea, demonstrating the feasibility of large-scale docking for ion channel drug discovery. more...
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- 2024
18. The SAFT for prediction of hydrate formation conditions of gas mixtures in the presence of methane, glycerol, ethylene glycol, and triethylene glycol
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Kou, Xuan and Li, Xiao-Sen
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- 2019
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19. Docking and structure activity relationship studies of potent and selective thiazolidinethione GSK-3 inhibitors
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Boesger, Hannah, Williams, Kurtis, Abdullai, Sa Adatu, Hubble, Brianna, Noori, Mahboubeh S., Orac, Crina, Amesaki, Deborah K., Ghazanfari, Davoud, Fairchild, Emily A., Fatunbi, Opeyemi O., Pritchard, Joshua A., Goetz, Douglas J., Hines, Jennifer V., and Bergmeier, Stephen C. more...
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- 2025
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20. Small molecule targeting Na V 1.7 via inhibition of CRMP2-Ubc9 interaction reduces pain-related outcomes in a rodent osteoarthritic model.
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Hestehave, Sara, Allen, Heather N., Gomez, Kimberly, Duran, Paz, Calderon-Rivera, Aida, Loya-López, Santiago, Rodríguez-Palma, Erick J., and Khanna, Rajesh
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PATCH-clamp techniques (Electrophysiology) , *DORSAL root ganglia , *BEHAVIORAL assessment , *SODIUM channels , *SMALL molecules - Abstract
Supplemental Digital Content is Available in the Text. Compound 194 inhibits CRMP2 SUMOylation, indirectly regulating NaV1.7 to alleviate osteoarthritic pain. Osteoarthritis (OA) is a highly prevalent and disabling joint disease, characterized by pathological progressive joint deformation and clinical symptoms of pain. Disease-modifying treatments remain unavailable, and pain-mitigation is often suboptimal, but recent studies suggest beneficial effects by inhibition of the voltage-gated sodium channel NaV1.7. We previously identified compound 194 as an indirect inhibitor of NaV1.7 by preventing SUMOylation of the NaV1.7-trafficking protein, collapsin response mediator protein 2. Compound 194 reduces the functional activity of NaV1.7 channels and produces effective analgesia in a variety of acute and neuropathic pain models. However, its effectiveness has not yet been evaluated in models of OA. Here, we explore the effects of 194 on pain-related outcomes in the OA-like monoiodoacetate model using behavioral assessment, biochemistry, novel in vivo fiber photometry, and patch clamp electrophysiology. We found that the monoiodoacetate model induced (1) increased pain-like behaviors and calcium responses of glutamatergic neurons in the parabrachial nucleus after evoked cold and mechanical stimuli, (2) conditioned place aversion to mechanical stimulation, (3) functional weight bearing asymmetry, (4) increased sodium currents in dorsal root ganglia neurons, and (5) increased calcitonin gene–related peptide-release in the spinal cord. Crucially, administration of 194 improved all these pain-related outcomes. Collectively, these findings support indirect inhibition of NaV1.7 as an effective treatment of OA-related pain through the inhibition of collapsin response mediator protein 2-SUMOylation via compound 194. [ABSTRACT FROM AUTHOR] more...
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- 2025
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21. Epigenetic dysregulation in glioblastoma: potential pathways to precision medicine.
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Prakash, Vijeta and Gabrani, Reema
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The emerging field of epigenetics has been driving glioblastoma multiforme (GBM) development and progression. Various epigenetic alterations involving tumor suppressor genes, oncogenes, and signaling pathways have been identified in GBM. These alterations contribute to the aggressive behavior, therapeutic resistance, and tumor heterogeneity observed in GBM. Furthermore, the identification of specific genetic mutations associated with epigenetic dysregulation in GBM has provided new insights into the molecular subtypes and potential therapeutic targets within GBM. Understanding the complex interplay between genetic and epigenetic alterations in GBM is crucial for the development of effective and personalized therapies for this devastating disease. This review paper provides an overview of the epigenetic changes occurring in GBM and the potential of targeted epigenetic therapies as a promising avenue for GBM treatment, highlighting the challenges and future directions in this field has been deliberated. [ABSTRACT FROM AUTHOR] more...
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- 2025
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22. Development of a FUT8 Inhibitor with Cellular Inhibitory Properties.
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Manabe, Yoshiyuki, Takebe, Tomoyuki, Kasahara, Satomi, Hizume, Koki, Kabayama, Kazuya, Kamada, Yoshihiro, Asakura, Akiko, Shinzaki, Shinichiro, Takamatsu, Shinji, Miyoshi, Eiji, García‐García, Ana, Vakhrushev, Sergey Y., Hurtado‐Guerrero, Ramón, and Fukase, Koichi more...
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HIGH throughput screening (Drug development) , *FUCOSE , *FUCOSYLATION , *DRUG development , *STRUCTURAL optimization - Abstract
Core fucosylation is catalyzed by α‐1,6‐fucosyltransferase (FUT8), which fucosylates the innermost GlcNAc of N‐glycans. Given the association of FUT8 with various diseases, including cancer, selective FUT8 inhibitors applicable to in vivo or cell‐based systems are highly sought‐after. Herein, we report the discovery of a compound that selectively inhibits FUT8 in cell‐based assays. High‐throughput screening revealed a FUT8‐inhibiting pharmacophore, and further structural optimization yielded an inhibitor with a KD value of 49 nM. Notably, this binding occurs only in the presence of GDP (a product of the enzymatic reaction catalyzed by FUT8). Mechanistic studies suggested that this inhibitor generates a highly reactive naphthoquinone methide derivative at the binding site in FUT8, which subsequently reacts with FUT8. Furthermore, prodrug derivatization of this inhibitor improved its stability, enabling suppression of core fucose expression and subsequent EGFR and T‐cell signaling in cell‐based assays, paving the way for the development of drugs targeting core fucosylation. [ABSTRACT FROM AUTHOR] more...
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- 2024
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23. Elongation factor 2 in cancer: a promising therapeutic target in protein translation.
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Jia, Xuechao, Huang, Chuntian, Liu, Fangfang, Dong, Zigang, and Liu, Kangdong
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Aberrant elongation of proteins can lead to the activation of oncogenic signaling pathways, resulting in the dysregulation of oncogenic signaling pathways. Eukaryotic elongation factor 2 (eEF2) is an essential regulator of protein synthesis that precisely elongates nascent peptides in the protein elongation process. Although studies have linked aberrant eEF2 expression to various cancers, research has primarily focused on its structure, highlighting a need for deeper exploration into its molecular functions. In this review, recent advancements in the structure, guanosine triphosphatase (GTPase) activity, posttranslational modifications, regulatory factors, and inhibitors of eEF2 are summarized. These findings provide a comprehensive cognition on the critical role of eEF2 and its potential as a therapeutic target in cancer. Furthermore, this review highlights important unanswered questions that warrant investigation in future research. [ABSTRACT FROM AUTHOR] more...
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- 2024
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24. Glutamine transporters as effective targets in digestive system malignant tumor treatment.
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CHU, FEI, TONG, KAI, GU, XIANG, BAO, MEI, CHEN, YANFEN, WANG, BIN, SHAO, YANHUA, and WEI, LING
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INHIBITION of cellular proliferation ,DIGESTIVE organs ,GLUTAMINE ,AMINO acids ,TUMOR treatment - Abstract
Glutamine is one of the most abundant non-essential amino acids in human plasma and plays a crucial role in many biological processes of the human body. Tumor cells take up a large amount of glutamine to meet their rapid proliferation requirements, which is supported by the upregulation of glutamine transporters. Targeted inhibition of glutamine transporters effectively inhibits cell growth and proliferation in tumors. Among all cancers, digestive system malignant tumors (DSMTs) have the highest incidence and mortality rates, and the current therapeutic strategies for DSMTs are mainly surgical resection and chemotherapy. Due to the relatively low survival rate and severe side effects associated with DSMTs treatment, new treatment strategies are urgently required. This article summarizes the glutamine transporters involved in DSMTs and describes their role in DSMTs. Additionally, glutamine transporter-target drugs are discussed, providing theoretical guidance for the further development of drugs DSMTs treatment. [ABSTRACT FROM AUTHOR] more...
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- 2024
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25. Dental Considerations in Children with Inherited Bleeding Disorders and Inhibitors: A Systematic Review.
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Vujkov, Sanja, Bajkin, Branislav, Blagojević, Duška, Nešković, Isidora, Komšić, Jelena, Tadić, Ana, and Petrović, Bojan
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Background/Objectives: This systematic review evaluates the effectiveness of various hematological treatment protocols and local hemostatic measures in preventing oral bleeding and other complications during and after dental treatments in children with inherited bleeding disorders and inhibitors. Methods: This study was registered in the PROSPERO database. The comprehensive search strategy for this systematic review was conducted across five databases, namely, PubMed, Google Scholar, Web of Science, Scopus, and Cochrane Library. The search was aimed at identifying relevant literature published from January 2000 up to February 2024. Eligible studies included those with various designs, such as randomized controlled trials (RCTs), observational studies, cohort studies, case–control studies, and cross-sectional studies. Data extraction was carried out systematically, and relevant information on study characteristics, interventions, treatment protocols, local measures, complications, and outcomes was collected. Results: The systematic review included a total of five studies, encompassing participants ranging from ages of 2 to 18 years. These studies varied in their scope, with some focusing on hemophilia A with inhibitors while others addressed broader inherited bleeding disorders. The interventions examined included various prophylactic and treatment measures such as Emicizumab, recombinant factor VIIa, and local hemostatic measures. The study outcomes primarily assessed the efficacy of these interventions in preventing postoperative bleeding and improving quality of life. Emicizumab has significantly shifted the treatment paradigm for children with inherited bleeding disorders and inhibitors. This prophylactic treatment has been associated with a marked reduction in the frequency of bleeding episodes, fewer hospital admissions for bleeding management, and enhanced participation in daily activities. Conclusions: This review highlights gaps in the management of dental care in children with inherited bleeding disorders and inhibitors. It underscores the need for standardized protocols that integrate new prophylactic treatments such as Emicizumab. Our findings suggest that adopting updated protocols can significantly reduce bleeding complications during dental procedures. [ABSTRACT FROM AUTHOR] more...
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- 2024
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26. Design of Novel Thiazole‐based Schiff Analogs as α‐Amylase Inhibitors Using 3D‐QSAR, ADME‐Tox, Molecular Docking, Molecular Dynamics, Biological Efficacy, and Retrosynthesis.
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Naanaai, Lhoucine, Ouabane, Mohamed, Moukhliss, Youness, El Aissouq, Abdellah, Zaitan, Hicham, Bouachrine, Mohammed, and Khalil, Fouad
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SCHIFF base derivatives , *VIRTUAL high-throughput screening (Drug development) , *MOLECULAR dynamics , *MOLECULAR docking , *LIGANDS (Biochemistry) - Abstract
This study enabled us to develop new analogs of the Schiff thiazole base with high inhibitory activity against the α‐amylase enzyme as effective anti‐diabetic drug candidates. To this end, we used virtual screening methods such as 3D‐QSAR, molecular docking, ADMET properties, molecular dynamics simulation, biological efficacy, and retrosynthesis on selected Schiff thiazole base derivatives. The results of 3D‐QSAR modeling showed that the CoMSIA_DH model has excellent predictive ability (Q2 = 0.71, R2train = 0.978, R2test = 0.987, and SEE = 0.072). Using the template (17), we designed three new ligands with high inhibitory activities against the α‐amylase enzyme. ADMET predictions for designed molecules met Lipinski's rule and pharmacokinetic profiles. The new Ligands were anchored in α‐amylase's active site, showing good binding affinities. The molecular docking results and binding stability of the selected ligands to the receptor were confirmed through molecular dynamics simulations. The CaverDock program was utilized to identify the tunnels through which ligands are most likely to migrate from the active site to the receptor surface, thereby determining the biological efficacy of the target compounds. The study found compound B1 to be the most effective, and using retrosynthesis, a pathway for the synthesis of these therapeutic prospects was identified. [ABSTRACT FROM AUTHOR] more...
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- 2024
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27. Bleed treatment with eptacog beta (rFVIIa) results in a low incidence of rebleeding in adult and adolescent patients with haemophilia A or B with inhibitors.
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Dunn, Amy, Dargaud, Yesim, Abajas, Yasmina, Carcao, Manuel, Castaman, Giancarlo, Giermasz, Adam, Hermans, Cédric, Jiménez‐Yuste, Victor, Lewandowska, Magdalena, Mahlangu, Johnny, Meeks, Shannon, Miesbach, Wolfgang, Recht, Michael, Salinas, Vanessa, Chrisentery‐Singleton, Tammuella, Bonzo, Daniel, Mitchell, Ian S., Wilkinson, Thomas A., and Young, Guy more...
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HEMOPHILIACS , *PERIOPERATIVE care , *TREATMENT effectiveness , *HEMOPHILIA , *ADULTS - Abstract
Introduction Aim Methods Results Conclusion Eptacog beta is a novel human recombinant FVIIa approved for use in the United States, European Union, United Kingdom and Mexico for the treatment and control of bleeding in patients with haemophilia A or B with inhibitors (≥12 years). It is also indicated for perioperative care in the same patient population in Europe and the United Kingdom.To assess the incidence of rebleeding and review treatment outcomes in subjects with haemophilia with inhibitors enrolled in the phase 3 PERSEPT 1 clinical trial.To treat mild/moderate bleeding episodes (BEs), subjects administered an initial 75 or 225µg/kg dose of eptacog beta, followed (if necessary) by additional 75µg/kg doses at predefined intervals until bleed control. This analysis used subject‐reported rebleeding to determine a rebleeding incidence for the first 24 h. Rebleeding through later timepoints was an exploratory, intention‐to‐treat analysis of bleed treatment data.Four hundred and sixty‐five BEs were analysed. Through 24 h, the proportion of rebleeds was 0% (initial 75µg/kg dose) and 0.5% (initial 225µg/kg dose). Through 48 h, the proportion of rebleeds was 3.2% (75µg/kg initial dose) and 5.6% (225µg/kg initial dose); the difference between initial dose strategies was not statistically significant. The majority of rebleeds were controlled with a single dose of eptacog beta and no subject who treated a rebleed required hospitalization.Subjects with haemophilia with inhibitors who used eptacog beta to treat mild/moderate BEs experienced a low incidence of rebleeding. Rebleeds that did occur were effectively controlled with eptacog beta (median, one dose) without the need for hospitalization. [ABSTRACT FROM AUTHOR] more...
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- 2024
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28. Recent advances in dark fermentative hydrogen production from vegetable waste: role of inoculum, consolidated bioprocessing, and machine learning.
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Pengadeth, Devu, Basak, Nitai, Bernabò, Luca, and Adessi, Alessandra
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WASTE products as fuel ,SUSTAINABILITY ,ENVIRONMENTAL engineering ,HYDROGEN production ,FOOD supply - Abstract
Waste-centred-bioenergy generation have been garnering interest over the years due to environmental impact presented by fossil fuels. Waste generation is an unavoidable consequence of urbanization and population growth. Sustainable waste management techniques that are long term and environmentally benign are required to achieve sustainable development. Energy recovery from waste biomass via dark fermentative hydrogen production is a sustainable approach to waste management. Vegetable waste is generated in plenty over the food supply chain and being a rich source of carbon and other nutrients it has been studied for production of biohydrogen. This review aims to offer a comprehensive overview on the potential of vegetable waste as a feedstock for dark fermentative biohydrogen production. The hydrogen output from dark fermentative process is lower and additional strategies are required to improve the production. This review addresses the challenges generally encountered during dark fermentative hydrogen production using vegetable waste and the importance of methods such as bioaugmentation and application of extremophiles for process enhancement. The role of machine learning in the field of biohydrogen production is briefly discussed. The application of dark fermentative effluents for secondary valuable product generation and its contribution to the biohydrogen biorefinery is discussed as well. [ABSTRACT FROM AUTHOR] more...
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- 2024
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29. Expedited SARS‐CoV‐2 Main Protease Inhibitor Discovery through Modular ‘Direct‐to‐Biology’ Screening.
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Wilders, Harry, Biggs, George, Rowe, Sam M., Cawood, Emma E., Riziotis, Ioannis G., Rendina, Alan R., Grant, Emma K., Pettinger, Jonathan, Fallon, David J., Skehel, Mark, House, David, Tomkinson, Nicholas C. O., and Bush, Jacob T. more...
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BIOLOGICAL assay , *PHARMACEUTICAL chemistry , *LIGANDS (Chemistry) , *DRUG target , *SARS-CoV-2 - Abstract
Reactive fragment (RF) screening has emerged as an efficient method for ligand discovery across the proteome, irrespective of a target's perceived tractability. To date, however, the efficiency of subsequent optimisation campaigns has largely been low‐throughput, constrained by the need for synthesis and purification of target compounds. We report an efficient platform for ‘direct‐to‐biology’ (D2B) screening of cysteine‐targeting chloroacetamide RFs, wherein synthesis is performed in 384‐well plates allowing direct assessment in downstream biological assays without purification. Here, the developed platform was used to optimise inhibitors of SARS‐CoV‐2 main protease (MPro), an established drug target for the treatment of COVID‐19. An initial RF hit was developed into a series of potent inhibitors, and further exploration using D2B screening enabled a ‘switch’ to a reversible inhibitor series. This example of ligand discovery for MPro illustrates the acceleration that D2B chemistry can offer for optimising RFs towards covalent inhibitor candidates, as well as providing future impetus to explore the evolution of RFs into non‐covalent ligands. [ABSTRACT FROM AUTHOR] more...
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- 2024
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30. Synergistic role of Rubisco inhibitor release and degradation in photosynthesis.
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Pasch, Viviana, Leister, Dario, and Rühle, Thilo
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ARABIDOPSIS thaliana , *CARBON fixation , *SUGAR phosphates , *PLANT growth , *BINDING sites - Abstract
Summary Ribulose‐1,5‐bisphosphate carboxylase/oxygenase (Rubisco) exhibits catalytic promiscuity, resulting in error‐prone reactions and the formation of inhibitory sugar phosphates. Specifically, Xylulose‐1,5‐bisphosphate (XuBP) acts as an inhibitor by binding to the active site of Rubisco, thereby impairing its catalytic function. Thermolabile Rubisco activase (Rca) facilitates the release of such inhibitors, including XuBP, by remodelling Rubisco. In Arabidopsis thaliana, the phosphatase pair CbbYA and CbbYB subsequently hydrolyses XuBP to prevent its rebinding to Rubisco. To explore the functional interplay between these components in maintaining photosynthesis, cbbya, cbbyb and cbbyab mutants were crossed with RCA knockdown (rca‐2) lines. Additionally, both RCA and CBBYA were overexpressed in wild‐type (WT) Arabidopsis thaliana. Phenotypic analyses revealed an exacerbation in decreased growth and photosynthetic efficiency in the cbbyab rca‐2 double mutants compared with the control mutants (cbbyab and rca‐2), indicating a negative genetic interaction. Furthermore, the co‐overexpression of RCA and CBBYA did not improve photosynthesis under short‐term heat stress, and light reactions were adversely affected relative to the WT. These findings illustrate the synergistic roles of Rca, CbbYA and CbbYB in maintaining carbon fixation and promoting plant growth in Arabidopsis thaliana. Thus, the coordinated regulation of Rca and CbbY enzymes is crucial for optimizing photosynthetic efficiency. [ABSTRACT FROM AUTHOR] more...
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- 2024
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31. MetAP2 as a Therapeutic Target for Obesity and Type 2 Diabetes: Structural Insights, Mechanistic Roles, and Inhibitor Development.
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Moon, Dong Oh
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Type 2 Diabetes Mellitus (T2DM) and obesity are globally prevalent metabolic disorders characterized by insulin resistance, impaired glucose metabolism, and excessive adiposity. Methionine aminopeptidase 2 (MetAP2), an intracellular metalloprotease, has emerged as a promising therapeutic target due to its critical role in regulating lipid metabolism, energy balance, and protein synthesis. This review provides a comprehensive analysis of MetAP2, including its structural characteristics, catalytic mechanism, and functional roles in the pathophysiology of T2DM and obesity. The unique architecture of MetAP2's active site and its interactions with substrates are examined to elucidate its enzymatic function. The review also explores the development of MetAP2 inhibitors, focusing on their mechanisms of action, preclinical and clinical findings, and therapeutic potential. Special emphasis is placed on docking studies to analyze the binding interactions of six key inhibitors (fumagillin, TNP-470, beloranib, ZGN-1061, indazole, and pyrazolo[4,3-b]indole) with MetAP2, revealing their structural determinants for efficacy and specificity. These findings underscore the potential of MetAP2 as a therapeutic target and provide valuable insights for the rational design of next-generation inhibitors to address obesity and T2DM. [ABSTRACT FROM AUTHOR] more...
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- 2024
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32. Expansion of the Structure–Activity Relationship Profile of Triaminopyrimidines as Inhibitors of Caspase‐1.
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East, Amanda, Polasek, Callista G., Miller, Elizabeth A., Ranganathan, Srirajkumar, Reda, Isabella D., Patel, Aisha, Ahlers, Christopher D., Zingales, Sarah K., and Karver, Caitlin E.
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Caspase‐1 is a sought‐after therapeutic target for inflammatory conditions due to its role in activation and release of pro‐inflammatory cytokines, but there has been little success getting drugs into the clinic. We have previously shown triaminopyrimidines such as CK‐1‐41 are potent, reversible small molecule inhibitors of caspase‐1, likely binding in an allosteric site within the enzyme. A series of analogs of CK‐1‐41 were synthesized and tested against caspase‐1 to develop a more robust structure–activity relationship profile. In general, alkyl and aryl groups were well tolerated via an ethylene or methylene linkage to the piperazine nitrogen, with IC50 values ranging from 13 to 200 nM. The most potent compounds were methylene linked o‐tolyl (AE‐2‐21) and ethylene linked 4‐trifluoromethylphenyl (AE‐2‐48) with IC50 values of 18 and 13 nM, respectively. Derivatives with electrophilic covalent warheads linked via an amide bond to the piperazine nitrogen were synthesized and characterized. CA‐1‐11 and EM‐1‐10 were semi‐reversible, non‐competitive inhibitors of caspase‐1 with slightly reduced potencies of 134 and 144 nM, respectively. All derivatives docked well into the allosteric site, supporting our hypothesis that this family of caspase‐1 inhibitors function via an allosteric non‐competitive mechanism of inhibition. [ABSTRACT FROM AUTHOR] more...
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- 2024
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33. A Phenomenological Qualitative Study Protocol and Semi‐Structured Interview Guide Development to Identify Perceptions, Experiences, Facilitators and Inhibitors in Patients With Knee Osteoarthritis Undergoing Rehabilitation in a Low‐ and Middle‐Income Country
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Bathran, Chandra and Samuel, Asir John
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Background: Perceptions, experiences, facilitators, and inhibitors of disease among patients may be shaped by their lifestyle and cultural background. Despite the significance of understanding their perspectives and experiences about disease for the prevention and management of osteoarthritis (OA) through physiotherapy, this subject has not been explored among patients with knee OA (PKOA) from lower and middle‐income countries (LMICs). Purpose: This study aims to explore the perception, and experiences of knee OA and physiotherapy treatment and identify the facilitators and inhibitors of physiotherapy treatment in PKOA from a lower‐ and middle‐income country, India. Method: 40 PKOA (n = 10 in each Kellgren and Lawrence grade) will be recruited using a purposive sampling technique. Data will be collected through semi‐structured interviews which are composed of pre‐determined open‐ended questions. Based on patients' flexibility and feasibility, the interview will be conducted face‐to‐face or by telephone or videoconference. The interview will be recorded using a digital audio recorder. Recorded data will be transcribed verbatim. Data will be analysed using thematic analysis based on the Braun and Clark approach. Results: The verbatim transcript will be evaluated to identify sub‐themes and themes through thematic analysis. Generated data will be investigated through inductive qualitative analysis to examine the viewpoints of PKOA. Conclusion: This study will explore the patients' perspectives, experiences, and the factors which will facilitate and inhibit the physiotherapy treatment for knee osteoarthritis. The result might reveal a new way to promote insightful decision‐making towards physiotherapy care for PKOA and help to improve their access to physiotherapy care. [ABSTRACT FROM AUTHOR] more...
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- 2024
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34. Real-world long-term safety and effectiveness of turoctocog alfa in the treatment of haemophilia A in Japan: results from a multicentre, non-interventional, post-marketing study.
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Nagao, Azusa, Deguchi, Ayumi, and Nogami, Keiji
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BLOOD coagulation factor VIII antibodies , *HEMOPHILIACS , *BLOOD coagulation factor VIII , *HEMOPHILIA treatment , *HEMOPHILIA - Abstract
Objectives: To assess the safety and effectiveness of turoctocog alfa in previously treated patients (PTPs) and previously untreated patients (PUPs) with haemophilia A in a real-world setting in Japan. Methods: This multicentre, non-interventional, post-marketing study recruited patients with haemophilia A who initiated treatment with turoctocog alfa from 18 sites (08/2014-12/2018). The primary endpoint was adverse events (AEs) during the 2-year study period. Results: The safety and effectiveness analysis set included 39 patients. In total, 13 (33.3%) patients reported ≥1 AE; incidence rate was 60.4 events/100 patient-years of exposure (PYE). Treatment was withdrawn in two cases: pruritus in a PTP and factor VIII inhibitor development in a PUP. Inhibitor development occurred in 2.6% of all patients, with an incidence rate of 3.8 events/100 PYE. The rate of inhibitor development was 0%, 25% and 20% in PTPs, PUPs and PUPs with severe type, respectively. The haemostatic success rate was 91.4% for 383 bleeding episodes and 85.7% for 14 surgeries. The negative binomial annualised bleeding rate for the prophylaxis regimen was 6.19 episodes/year (95% CI, 3.69–10.38). The mean (SD) total consumption of turoctocog alfa (n = 34; excluding FVIII inhibitors) was 5,382.6 (7,180.1) IU/kg/year/patient; consumption was 4,133.1 (1,452.4) IU/kg/year/patient for prophylaxis. Discussion: The effectiveness and safety profiles were comparable to those observed in other turoctocog alfa trials; effectiveness analysis and consumption were not affected by treatment regimens. Conclusion: Long-term use of turoctocog alfa therapy in clinical practice posed no newly identified safety issues and was effective for prophylaxis and treatment of bleeds in patients with haemophilia A in Japan. [ABSTRACT FROM AUTHOR] more...
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- 2024
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35. Development and safety of investigational and approved drugs targeting the RAS function regulation in RAS mutant cancers.
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Li, Jinjin, Wu, Wentong, Chen, Jiajia, Xu, Zhifei, Yang, Bo, He, Qiaojun, Yang, Xiaochun, Yan, Hao, and Luo, Peihua
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RAS oncogenes , *GENE families , *INVESTIGATIONAL drugs , *CANCER treatment , *CARCINOGENESIS - Abstract
The RAS gene family holds a central position in controlling key cellular activities such as migration, survival, metabolism, and other vital biological processes. The activation of RAS signaling cascades is instrumental in the development of various cancers. Although several RAS inhibitors have gained approval from the US Food and Drug Administration for their substantial antitumor effects, their widespread and severe adverse reactions significantly curtail their practical usage in the clinic. Thus, there exists a pressing need for a comprehensive understanding of these adverse events, ensuring the clinical safety of RAS inhibitors through the establishment of precise management guidelines, suitable intermittent dosing schedules, and innovative combination regimens. This review centers on the evolution of RAS inhibitors in cancer therapy, delving into the common adverse effects associated with these inhibitors, their underlying mechanisms, and the potential strategies for mitigation. [ABSTRACT FROM AUTHOR] more...
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- 2024
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36. Gigantolevisins A–C, tyrosinase inhibitory benzylidenes from the shoots of Gigantochloa levis.
- Author
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Sagaral-Lacandalo, Lina, Gelani, Chona D., Ohta, Emi, and Ohta, Shinji
- Abstract
The excessive tyrosinase activity has been linked to the overproduction of melanin which can lead to hyperpigmentation, oxidative stress, browning, and an increased risk of melanoma. Due to these detrimental effects associated with the overexpression of tyrosinase, research efforts are focused on finding bioactive compounds that can inhibit this enzyme efficiently. This study, conducted to find tyrosinase inhibitors utilizing the shoots of Gigantochloa levis (G. levis), produced three previously undescribed benzylidene derivatives (1–3) and two known compounds, with promising anti-tyrosinase activity. The new compounds were designated as gigantolevisins A–C, and the two known compounds as (E)-3-(4-hydroxyphenyl)-2-phenylacrylaldehyde (4) and (E)-2,3-bis(4-hydroxyphenyl)acrylaldehyde (5), respectively, based on the spectroscopic data and X-ray crystallographic analysis. The isolated compounds showed inhibition effects against tyrosinase, ranging from 42 % to 58 % (IC 50 values of >400–286 ± 15 μM) in comparison to the positive control Kojic acid with 100 % inhibition (IC 50 value of 43 ± 3 μM). The findings suggest that, while the isolated compounds are less potent than Kojic acid, they can be effective in inhibiting tyrosinase activity. Thus, the study highlights the therapeutic potential of G. levis shoots for treating melanin-related conditions. [Display omitted] • Three new benzylidene derivatives were isolated from the shoots of Gigantochloa levis. • Their structures were elucidated based on analysis of their spectroscopic data. • The isolated compounds exhibited inhibitory activity against the enzyme tyrosinase. • A possible biosynthetic pathway is proposed. [ABSTRACT FROM AUTHOR] more...
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- 2024
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37. Mycobacterium tuberculosis F-ATP Synthase Inhibitors and Targets.
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Harikishore, Amaravadhi and Grüber, Gerhard
- Abstract
Mycobacteria tuberculosis (Mtb) infection causes tuberculosis (TB). TB is one of the most intractable infectious diseases, causing over 1.13 million deaths annually. Under harsh growing conditions, the innate response of mycobacteria is to shut down its respiratory metabolism to a basal level, transit into a dormant, non-replicating phase to preserve viability, and establish latent infection. Mtb utilizes non-canonical regulatory mechanisms, such as alternative oxidase pathways, to survive in low oxygen/nutrient conditions. The bacterium's survival in its native microenvironmental niches is aided by its ability to evolve mutations to drug binding sites, enhance overexpression of various enzymes that activate β-lactam antibiotics hydrolysis, or stimulate efflux pathways to ward off the effect of antibiotics. Bedaquiline and its 3,5-dialkoxypyridine analogs, sudapyridine and squaramide S31f, have been shown to be potent Mtb F
1 FO -ATP synthase inhibitors of replicating and non-replicating Mtb and have brought oxidative phosphorylation into focus as an anti-TB target. In this review, we attempt to highlight non-canonical structural and regulatory pathogen-specific epitopes of the F1 -domain, ligand development on such sites, structural classes of inhibitors targeting the Fo-domain, and alternative respiratory metabolic responses that Mtb employs in response to bedaquiline to ensure its survival and establish latent infection. [ABSTRACT FROM AUTHOR] more...- Published
- 2024
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38. Influence of Cigarette Butt Extract on the Suppression of Metal Corrosion.
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Šućurović, Verena, Vladislavić, Nives, and Rončević, Ivana Škugor
- Abstract
Cigarette butts are an increasing environmental burden worldwide, and the quantities discarded each year could continue to rise. The chemical composition of cigarette butts, which comprises about 4000 different toxic chemicals, as well as their persistence in the environment and their potential negative effects pose a major threat to the environment as they regularly enter aquatic habitats and endanger water supplies and aquatic species. One effective way to reduce pollution is to recycle cigarette butts. The aim of this study is to evaluate the possibility of using extracts from cigarette butts (filter extract and extract from tobacco residues) as corrosion inhibitors for the Cu10Ni alloy in a 3.5% NaCl solution with a pH of 8 at different temperatures (12 °C, 20 °C and 25 °C). The determination of the electrochemical parameters, i.e., the corrosion behavior of the Cu10Ni alloy in a 3.5% NaCl solution and pH of 8, with and without modification of the alloy surface by cigarette butt extracts was tested using electrochemical measurements (electrochemical impedance spectroscopy and linear and potentiodynamic polarization methods). The surface properties of the Cu10Ni alloy modified with cigarette butt extracts were evaluated by goniometry, SEM analysis and FTIR spectrophotometry. The modification of the surface of the Cu10Ni alloy with an extract of tobacco residue and a filter extract separated from cigarette butts, whose presence on the surface was confirmed by the surface analysis methods, increased the corrosion resistance of the alloy, indicating that these substances have an inhibitory effect. The better inhibition properties (at all temperatures: 12 °C, 20 °C and 25 °C) were exhibited by the filter extract, and the highest inhibition effect was exhibited by the filter extract at 12 °C. [ABSTRACT FROM AUTHOR] more...
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- 2024
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39. Motivations and inhibitors to blood donation.
- Author
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Silva Carlos, Vera and Rodrigues, Ricardo Gouveia
- Abstract
Considering the small percentage of blood donors and that it is common for individuals who donate blood for the first time not to repeat the donation in the future, the continuous need for blood remains a global challenge. For these reasons, blood donation centres need to understand the aspects that motivate people to donate blood and those that discourage this behaviour. Hence, our research goal is to identify the aspects that contribute to donation and those that demotivate it. A total of 540 questionnaires were gathered, and t-tests were used to compare dimensions of Altruism regarding donors, and motivations and inhibitors, as well as the perception regarding incentives to blood donation, among nondonors and potential donors. We conclude that donors are mainly motivated by the attainment of warm glow from benefiting others and that they show preferential helping towards family. Our study suggests that potential blood donors are willing to donate, but may not do so due to perceived barriers, primarily the fear of falling unconscious, becoming nauseous/weak and of the transmission of infectious diseases –, and the lack of knowledge regarding the existence of incentives to blood donation. Therefore, social marketing campaigns for donor retention should be focused on the emotional reward gained by benefiting others, particularly family, and recruitment should be aimed at potential donors, with focus on changing perceptions regarding the identified inhibitors and on giving more information about incentives for blood donors. Our study contributes to previous research by identifying some particular aspects related to nondonors that have higher potential to become donors, and kinship as a strong motivation for donors, unlike previous studies in this area. [ABSTRACT FROM AUTHOR] more...
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- 2024
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40. Omniphobic/superhydrophobic surface effect on oil and gas flow: A critical review.
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Hasan, Mehedi, Sun, Baojiang, Bahaeddine, Mihoubi, Liang, Youran, Damulira, Moses, and Chen, Litao
- Subjects
PETROLEUM ,SUPERHYDROPHOBIC surfaces ,GAS flow ,GAS industry ,PETROLEUM industry ,ASPHALTENE - Abstract
Flow assurance in the petroleum business of the oil and gas industry ensures the efficient and continuous flow of hydrocarbons from production facilities to consumers. Impurities in oil and gas can cause corrosion and erosion, hydrate formation, scaling, and fouling, resulting in flow limits and reduced operating efficiency. The significant flow assurance issues must be managed through systematic exploration of effective mitigation and management approaches. The objective of this paper is to highlight the latest research in the field of flow assurance, including the application of superhydrophobic or omniphobic coatings to prevent scale growth, asphaltene precipitation, wax deposition, and hydrate formation. This review will provide new perspectives into the basic mechanistic mechanisms of deposition and blockage in oil and gas production systems, assisting in the development of novel methods compared to the employment of commercial chemical or mechanical techniques. Overall, the flow assurance engineers will gain new perspectives from this study regarding how to deal with the risk of pipeline blockage caused by the problems mentioned earlier. [ABSTRACT FROM AUTHOR] more...
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- 2024
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41. Decoding the conundrum: exploring complex interlinkages between mobile wallet adoption inhibitors among unorganised retailers.
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Kapoor, Ashwarya, Sindwani, Rajiv, and Goel, Manisha
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ELECTRONIC wallets ,MOBILE commerce ,GROWTH industries ,DEVELOPING countries ,COLLEGE teachers - Abstract
The success of mobile wallet (m-wallet) in developing countries depends upon a great extent to its adoption among unorganised retailers. The adoption among them is still in its nascent stage due to presence of various inhibitors. Using innovation resistance theory as underpinning theory, this pioneer study attempts to identify an exhaustive set of m-wallet adoption inhibitors among unorganised retailers and to analyse the complex inter-relationship among them. Total thirteen inhibitors are identified through an extensive literature review and discussion with unorganised retailers. Further, an integrated DEMATEL and ISM-MICMAC approach is used to assess the complex inter-linkage among inhibitors. DEMATEL results disclosed 'preference for cash' and 'early adoption hesitation' as effect barriers and rest other eleven as cause barriers. ISM results revealed complex inter-relationship among identified barriers through an eight level hierarchical interpretive model. Further, ISM is complemented by MICMAC analysis that segregated the inhibitors into four distinct quadrants namely autonomous, independent, linkage and dependent on the basis of their driving power and dependencies. The application of the hybrid approach used in this study is novel in the domain of mobile payments. Findings of the study provide useful insights for both academicians and practitioners. Academically, this study enriches literature on m-wallet adoption. Practically, this study offers useful insights to marketers for growth of m-wallet industry. [ABSTRACT FROM AUTHOR] more...
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- 2024
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42. Simulating New Fusidic Acid Derivatives to Target Gram‐Positive Bacteria by Using Computational Methods.
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Hossain, Md. Shamim, Sakib, Mohiuddin, Rahman, Shofiur, Al‐Gawati, Mahmoud A., Alodhayb, Abdullah N., Albrithen, Hamad, Hossain, Md. Mainul, Poirier, Raymond A., and Uddin, Kabir M.
- Subjects
- *
ELONGATION factors (Biochemistry) , *MOLECULAR dynamics , *DENSITY functional theory , *ACID derivatives , *MOLECULAR docking - Abstract
Gram‐positive bacteria represent a significant threat due to their resistance to conventional antibiotics. This study employs computational methods to investigate fusidic acid (FA) derivatives (1–24) as potential antibiotics against Gram‐positive bacteria. Techniques such as density functional theory calculations, molecular docking, and molecular dynamics simulations were utilized to evaluate ligand interactions with target proteins Staphylococcus aureus (S. aureus) elongation factor G (fusA) (2XEX), fusidic acid resistance protein (fusB) (4ADN), and fusidic acid resistance protein (fusC) (2YB5), comparing them to established antibiotics (ceftobiprole, linezolid, vancomycin). Notably, ligand 16 demonstrated a remarkable binding affinity to the S. aureus elongation factor G protein (−8.7 kcal mol⁻¹), closely aligning with both in vitro and in vivo results and outperforming fusidic acid and reference drugs. In silico methods (SwissADME, AdmetSAR, Molinspiration, Molsoft) were used to assess pharmacokinetics and drug‐likeness. Molecular dynamics (MD) simulations confirmed superior S. aureus elongation factor G stability for ligands fusidic acid 1, (Z)‐2‐((3R,4S,8S,9R,10S,11R,13S,14S,16S)‐16‐acetoxy‐3,11‐dihydroxy‐4,8,10,14‐tetramethylhexadecahydro‐17H‐cyclopenta[a]phenanthren‐17‐ylidene)‐5‐cyclohexylidene‐ pentanoic acid (14), (Z)‐2‐((3R,4S,8S,9R,10S,11R,13S, 14S,16S)‐16‐acetoxy‐3,11‐dihydroxy‐4,8,10,14‐tetramethylhexadecahydro‐17H‐cyclopenta[a]phenanthren‐17‐ylidene)‐5cyclohexylidenepentanoic acid (16), and (Z)‐2‐((3R,4S,8S,9R,10S,11R,13S,14S,16S)‐16‐acetoxy‐3,11‐dihydroxy‐4,8,10,14‐tetramethylhexadecahydro‐17H‐cyclopenta[a]phenanthren‐17‐ylidene)‐5‐cyclopentylidenepentanoic acid (17), with ligand 16 exhibiting exceptional stability across various temperatures, especially at human body temperature (310 K). Further molecular dynamics simulations of ligand 16 validated its robust stability and potential to disrupt S. aureus elongation factor G, supporting the docking results and showing strong consistency with in vitro and in vivo findings. Consequently, ligand 16 emerges as a promising candidate for further development as an anti‐Gram‐positive bacterial drug, pending validation through rigorous clinical trials. [ABSTRACT FROM AUTHOR] more...
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- 2024
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43. Unveiling the role of histone deacetylases in neurological diseases: focus on epilepsy.
- Author
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Cao, Dan-Feng, Zhou, Xin-Yu, Guo, Qian, Xiang, Ming-Yao, Bao, Mei-Hua, He, Bin-Sheng, and Mao, Xiao-Yuan
- Subjects
DRUG discovery ,NEUROLOGICAL disorders ,GENETIC transcription ,REGULATOR genes ,HISTONE deacetylase inhibitors - Abstract
Epilepsy remains a prevalent chronic neurological disease that is featured by aberrant, recurrent and hypersynchronous discharge of neurons and poses a great challenge to healthcare systems. Although several therapeutic interventions are successfully utilized for treating epilepsy, they can merely provide symptom relief but cannot exert disease-modifying effect. Therefore, it is of urgent need to explore other potential mechanism to develop a novel approach to delay the epileptic progression. Since approximately 30 years ago, histone deacetylases (HDACs), the versatile epigenetic regulators responsible for gene transcription via binding histones or non-histone substrates, have grabbed considerable attention in drug discovery. There are also substantial evidences supporting that aberrant expressions and/activities of HDAC isoforms are reported in epilepsy and HDAC inhibitors (HDACi) have been successfully utilized for therapeutic purposes in this condition. However, the specific mechanisms underlying the role of HDACs in epileptic progression have not been fully understood. Herein, we reviewed the basic information of HDACs, summarized the recent findings associated with the roles of diverse HDAC subunits in epilepsy and discussed the potential regulatory mechanisms by which HDACs affected the development of epilepsy. Additionally, we also provided a brief discussion on the potential of HDACs as promising therapeutic targets for epilepsy treatment, serving as a valuable reference for basic study and clinical translation in epilepsy field. [ABSTRACT FROM AUTHOR] more...
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- 2024
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44. Exploring the Effect of Resveratrol, Tyrosol, and Their Derivatives on Platelet-Activating Factor Biosynthesis in U937 Cells.
- Author
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Petsini, Filio, Detopoulou, Maria, Choleva, Maria, Kostakis, Ioannis K., Fragopoulou, Elizabeth, and Antonopoulou, Smaragdi
- Subjects
- *
MITOGEN-activated protein kinases , *PHENOLS , *OLIVE oil , *ACETYLTRANSFERASES , *RESVERATROL - Abstract
Platelet-activating factor (PAF) is a potent lipid mediator, involved in thrombosis, inflammation, and atherosclerosis. The protective effect of wine and olive oil against atherosclerotic diseases is largely attributed to their phenolic compounds and mostly to resveratrol and tyrosol. Both compounds have been reported to inhibit PAF biosynthesis in interleukin-1β (IL-1β)-stimulated monocytes and also to attenuate PAF biosynthesis in cell lysates. The aim of this study was to investigate the effects of resveratrol, tyrosol, and their derivatives on unstimulated U937 cells and to explore the intracellular messaging pathways that participate in the activation of PAF biosynthesis in the same cell line. Tyrosol and its derivatives did not exert any substantial effect on PAF biosynthesis. Resveratrol (50 and 100 μM), as well as its methoxy derivative (5–20 μM), caused a reduction in the PAF biosynthetic enzymes' activity by 20–43% after 24 h of incubation. On the other hand, lower resveratrol concentration (10 μM) and higher concentration of the methoxy derivative (50 μM) increased the Ca2+-dependent lyso–PAF acetyltransferase (LysoPAF-ATC) activity by 28–45% after half-hour incubation via p38 mitogen-activated protein kinase (p38-MAPK) action. IL-1β activated PAF biosynthetic pathways via different signaling pathways, with phospholipase C-β (PLC-β) being a key enzyme. [ABSTRACT FROM AUTHOR] more...
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- 2024
- Full Text
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45. Targeting Vascular Endothelial Growth Factor Receptor 2 (VEGFR-2): Latest Insights on Synthetic Strategies.
- Author
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Marques, Carolina S., Brandão, Pedro, and Burke, Anthony J.
- Subjects
- *
VASCULAR endothelial growth factor receptors , *DRUG development , *DRUG resistance , *CANCER invasiveness , *DRUG synthesis - Abstract
Vascular endothelial growth factor receptor 2 (VEGFR-2) is a crucial mediator of angiogenesis, playing a pivotal role in both normal physiological processes and cancer progression. Tumors harness VEGFR-2 signaling to promote abnormal blood vessel growth, which is a key step in the metastasis process, making it a valuable target for anticancer drug development. While there are VEGFR-2 inhibitors approved for therapeutic use, they face challenges like drug resistance, off-target effects, and adverse side effects, limiting their effectiveness. The quest for new drug candidates with VEGFR-2 inhibitory activity often starts with the selection of key structural motifs present in molecules currently used in clinical practice, expanding the chemical space by generating novel derivatives bearing one or more of these moieties. This review provides an overview of recent advances in the development of novel VEGFR-2 inhibitors, focusing on the synthesis of new drug candidates with promising antiproliferative and VEGFR-2 inhibition activities, organizing them by relevant structural features. [ABSTRACT FROM AUTHOR] more...
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- 2024
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46. Role of Metalloproteinases in Adhesion to Radicular Dentin: A Literature Review.
- Author
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Valdez-Montoya, Marihana, Avendaño-Félix, Mariana Melisa, Basurto-Flores, Julio César, Ramírez-Álvarez, Maricela, Cázarez-Camacho, María del Rosario, Casillas-Santana, Miguel Ángel, Zavala-Alonso, Norma Verónica, Sarmiento-Hernández, Seyla Nayjaá, Silva-Benítez, Erika de Lourdes, and Soto-Sainz, Jesús Eduardo more...
- Subjects
- *
PROTEOLYTIC enzymes , *TISSUE remodeling , *DENTIN , *EXTRACELLULAR matrix , *METALLOPROTEINASES , *ADHESION - Abstract
Introduction: Root dentin is a porous and complex dental surface that may have irregularities and deposits of organic material. To achieve an effective bond between restorative materials and root dentin, it is necessary that the restorative materials adhere intimately to the dentin surface. Metalloproteinases (MMPs) are a group of proteolytic enzymes that perform an important role in degrading the extracellular matrix and remodeling connective tissue. The aim of this research was to determine the scientific evidence available on the role played by MMPs in adhesion to root dentin and their putative inhibitors. Materials and Methods: Several techniques have been used to evaluate the presence of MMPs in the root dentin of human and bovine teeth, such as Western blot, immunohistochemistry, immunofluorescence, and zymography, the latter also being used together with the EnzCheck assay to evaluate the inhibitory effect of adhesion protocols on the activity of root MMPs in vitro. Results: When analyzing the databases, 236 articles were found, 12 of which met the selection criteria. The variables analyzed were articles that evaluated different MMP inhibitors in root dentin. Conclusions: In the adhesion to radicular dentin, MMPs have a crucial role in the degradation of the extracellular matrix of dentin and the remodeling of the dentin surface because excessive MMP activity can be harmful to dental health, since excessive degradation of the extracellular matrix of dentin can weaken the tooth structure and decrease fracture resistance. Therefore, it is important to monitor MMP activity during root dentin bonding procedures. [ABSTRACT FROM AUTHOR] more...
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- 2024
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47. An experimental study on the effect of alumina nanocomposites on asphaltene precipitation.
- Author
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Mbouopda Poupi, Albert Brandt, Nchimi, Katia, Nguele, Ronald, Iqbal, Muhammad, Poulose, Vijo, Sasaki, Kyuro, and Saibi, Hakim
- Subjects
- *
HEAVY oil , *FERRIC chloride , *PETROLEUM , *ALUMINUM chloride , *STACKING interactions - Abstract
This study investigates the inhibition of asphaltene precipitation using alumina–iron nanocomposite (NCP). Al:Fe NCP, successfully synthesized from pure aluminum and iron chloride, is crystalline mixture of hematite and alumina phases with a purity of 99%. Decreasing the content in hematite lowers the particle size from ∼60 to 10 nm. To evaluate the inhibition potential of Al:Fe, a series of experiments consisting of the addition of Al:Fe NCP into a model crude oil followed by a precipitation using n-heptane were conducted. The model oil was a solution consisting of 3 mg of asphaltene extracted from a dead Middle Eastern heavy oil (29.2oAPI) dissolved into 10 g of toluene. 35 vol. % of heptane was required to precipitate asphaltene from the model crude oil. Hereinafter termed as asphaltene onset precipitation (AOP), adding 0.05 wt.% Al:Fe NCP to the model oil requires up to 30 mL of heptane to precipitate the same amount of asphaltenes. The increase in molar ratio in alumina decreases AOV up to 63.5%. The spectral studies revealed that the inhibition of asphaltene precipitation involves both the polar interactions of alumina phase with asphaltene and the decrease of the π–π stacking interaction upon addition of NCPs. [ABSTRACT FROM AUTHOR] more...
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- 2024
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48. Multifunctional, Fluorene‐Based Modulator of Cholinergic and GABAergic Neurotransmission as a Novel Drug Candidate for Palliative Treatment of Alzheimer's Disease.
- Author
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Panek, Dawid, Pasieka, Anna, Jończyk, Jakub, Gawlińska, Milena, Zaręba, Paula, Siwek, Agata, Wolak, Małgorzata, Mordyl, Barbara, Głuch‐Lutwin, Monika, Latacz, Gniewomir, Brazzolotto, Xavier, Chantegreil, Fabien, Nachon, Florian, Zdarova Karasova, Jana, Pejchal, Jaroslav, Mzik, Martin, Sestak, Vit, Prchal, Lukas, Odvarkova, Jitka, and Soukup, Ondrej more...
- Subjects
- *
GABA transporters , *ALZHEIMER'S disease , *ORAL drug administration , *MEMORY disorders , *MEMORY loss - Abstract
Alzheimer's disease (AD) is a neurodegenerative disorder characterized by memory loss and behavioral and psychological symptoms of dementia (BPSD). Given that cholinergic neurons are predominantly affected in AD, current treatments primarily aim to enhance cholinergic neurotransmission. However, imbalances in other neurotransmitters, such as γ‐aminobutyric acid (GABA), also contribute to AD symptomatology. In the presented research, using a combination of crystallography and computational methods we developed compound
6 as a dual modulator of GABAergic and cholinergic neurotransmission systems. Compound6 demonstrated inhibition of BuChE (IC50=0.21 μM) and GABA transporter 1 (IC50=10.96 μM) and 3 (IC50=7.76 μM), along with a favorable drug‐likeness profile. Subsequent in vivo studies revealed the effectiveness of6 in enhancing memory retention and alleviating anxiety and depression symptoms in animal models, while also proving safe and bioavailable for oral administration. The innovative multi‐target‐directed ligand6 offers a new approach to treating cognitive deficits and BPSD in AD. [ABSTRACT FROM AUTHOR] more...- Published
- 2024
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- View/download PDF
49. The regulating role of galectin-9 in immune cell populations.
- Author
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Cao, Zhanqi, Leng, Ping, Xu, Hanlin, and Li, Xiangpeng
- Subjects
CELL populations ,T cells ,NATURAL immunity ,THERAPEUTICS ,EOSINOPHILS - Abstract
Galectin-9 (gal-9) is a protein that belongs to the galectin family. Gal-9 is expressed in cells of the innate and adaptive immune system, including lymphocytes, dendritic cells, giant salivary cells, eosinophils and T cells, etc. In different immune cells, the role of gal-9 is different. Gal-9 can induce the proliferation and activation of immune cells, and also promote the apoptosis of immune cells. This effect of gal-9 affects the occurrence and development of a variety of immune-related diseases, such as the invasion of pathogenic microorganisms, immune escape of tumor cells, and inflammatory response. Thus, understanding the biological roles of gal-9 in innate and adaptive immunity may be essential for autoimmune diseases treatment and diagnosis to improve patient quality of life. In this review, we aim to summarize current research on the regulatory roles of gal-9 in human immune system and potential inducers and inhibitors of gal-9, which may provide new strategies for immune diseases therapies. [ABSTRACT FROM AUTHOR] more...
- Published
- 2024
- Full Text
- View/download PDF
50. Deciphering phosphodiesterase-5 inhibitors from Aframemum melegueta: computational models against erectile dysfunction.
- Author
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Omoboyowa, Damilola Alex
- Subjects
- *
PHOSPHODIESTERASE inhibitors , *PHOSPHODIESTERASE-5 inhibitors , *IMPOTENCE , *LEAD compounds , *QSAR models - Abstract
Insufficient and inability to maintain erection in male for satisfactory sexual performance remains global challenge among couples. The identification of phosphodiesterase-5 (PDE-5) antagonist in the pathogenesis of erectile dysfunction has improved the search for therapeutic agents for the management of this sexual dysfunction. Here in, bioactive compounds from Aframomum melegueta were virtually screened against PDE-5 using Schrodinger suite 2017-1 as computational tool. The lead compound was further validated in comparison with sildenafil by performing 100 ns molecular dynamics (MD) simulation using Desmond. Among 109 bioactive compounds screened, nine (9) molecules were predicted as potent inhibitors of PDE-5 with binding affinities comparable to the co-crystalized ligand (sildenafil). 1,7-bis(3,4-dihyroxy-5-methoxyphenyl)heptane-3,5-diyldiacetate was observed to have the best docking score (-11.522 kcal/mol) among the hit compounds which is very close to the co-crystalized ligand (-11.872 kcal/mol). Validation using pharmacophore hypothesis and QSAR modeling further confirmed the prediction of the hit compounds with fitness score ranging from 0.754 to 2.605 and predicted pIC50 of 3.835 to 7.976 µM. All the hit compounds obeyed Lipinski's rule of five and within the reference range of the pharmacokinetics parameters. The MD simulation result predicted the stability of 1,7-bis(3,4-dihydroxy-5-methoxyphenyl)heptane-3,5-diyldiacetate-PDE-5 complex comparable to the sildenafil-PDE-5 complex. The outcome of this study predicted nine molecules from A. melegueta as potent PDE-5 antagonists which required isolation and experimental validation for the management of erectile dysfunction. [ABSTRACT FROM AUTHOR] more...
- Published
- 2024
- Full Text
- View/download PDF
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