143 results on '"Ortuso F"'
Search Results
2. Design and synthesis of DNA-intercalating 9-fluoren-β- O-glycosides as potential IFN-inducers, and antiviral and cytostatic agents
- Author
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Alcaro, S, Arena, A, Neri, S, Ottanà, R, Ortuso, F, Pavone, B, and Vigorita, M.G
- Published
- 2004
- Full Text
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3. ANALYSIS OF THE PATHOGENETIC ROLE OF BRCA1 MISSENSE MUTATIONS IN HEREDITARY BREAST CANCER BY A MULTI- DISCIPLINARY APPROACH
- Author
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Cuda, G., Quaresima, B., Faniello, M., Baudi, F., Alcaro, S., Ortuso, F., Battaglia, D., Roriroti, D., Costanzo, F., and Venuta, S.
- Published
- 2003
4. Chiral 3,3′-(1,2-Ethanediyl)-bis[2-(3,4-dimethoxyphenyl)-4-thiazolidinones] with anti-inflammatory activity. Part 11: Evaluation of COX-2 selectivity and modelling
- Author
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Vigorita, M.G, Ottanà, R, Monforte, F, Maccari, R, Monforte, M.T, Trovato, A, Taviano, M.F, Miceli, N, De Luca, G, Alcaro, S, and Ortuso, F
- Published
- 2003
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5. Molecular modelling and enzymatic studies of acetylcholinesterase and butyrylcholinesterase recognition with paraquat and related compounds.
- Author
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Alcaro, S., Arcone, R., Vecchio, I., Ortuso, F., Gallelli, A., Pasceri, R., Procopio, A., and Iannone, M.
- Subjects
ENVIRONMENTAL research ,PARAQUAT ,BIPYRIDINIUM compounds ,QSAR models ,MOLECULAR models ,ACETYLCHOLINESTERASE ,BUTYRYLCHOLINESTERASE - Abstract
The potent herbicide paraquat and three other analogues MPP+, MPDP+ and MPTP have a known toxicological profile linked to the ability to damage dopaminergic neurons. Other biological effects were recently addressed to this class of compounds, including the ability to interact with enzymatic targets involved in the Central Nervous System, such as the acetylcholinesterase (AChE) and the butyrylcholinesterase (BuChE). A combined molecular modelling and enzymatic study focusing onto their interaction against the AChE and BuChE is reported. The former study was performed by docking techniques using target known co-crystallographic models. The latter study was carried out by the widely adopted Ellman's method. In both studies the anti-Alzheimer FDA approved drug tacrine was used as reference inhibitor. Our results indicate that paraquat, MPTP, MPDP+ and MPP+ recognize both enzymatic cleft in a similar fashion compared to the reference inhibitor. A structure-activity correlation was found with the net charge of the ligands, indicating a major role of the electrostatic term in the recognition and inhibition of these compounds. Our data completed their enzymatic profile, added new information on the molecular mechanisms underlying their neurotoxicity useful for the rational design of new cholinesterase inhibitors. [ABSTRACT FROM AUTHOR]
- Published
- 2007
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6. Theoretical Comparison between Structural and Dynamical Features of Dolastatins 11 and 12 Antineoplastic Depsipeptides.
- Author
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Alcaro, S., Marino, T., Ortuso, F., and Russo, N.
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ANTINEOPLASTIC agents ,STATINS (Cardiovascular agents) ,PEPTIDES ,ENZYME inhibitors ,PHARMACOLOGY ,DOLASTATIN - Abstract
Molecular mechanics (MM) and dynamics (MD) calculations in vacuo and in water have been performed for the natural cyclodepsipeptides Dolastatins 11 and 12 isolated from the sea hare Dolabella auricularia . The analysis of the MD trajectories for the two systems can give useful insight on the backbone structural features, side-chain and peptide-water interactions as well as on the inter- and intra-molecular hydrogen bonds. A comparison between the selected and analysed lowest energy isomers shows the different conformational behaviour of the compounds. Finally, with the aim to ascertain a structure-activity relationship for the two peptides, the interactions of both Dolastatins with water, generic hydrophobic environment, magnesium and calcium ions have been investigated by means of the GRID program. [ABSTRACT FROM AUTHOR]
- Published
- 2003
- Full Text
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7. Exploring Structural Requirements for Sigma-1 Receptor Linear Ligands: Experimental and Computational Approaches.
- Author
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Lombardo L, Mirabile S, Gitto R, Cosentino G, Alcaro S, Dichiara M, Marrazzo A, Amata E, Ortuso F, and De Luca L
- Subjects
- Ligands, Humans, Piperazines chemistry, Piperazines metabolism, Protein Binding, Binding Sites, Protein Conformation, Receptors, sigma metabolism, Receptors, sigma chemistry, Sigma-1 Receptor, Molecular Dynamics Simulation
- Abstract
Sigma-1 receptor (S1R) is involved in a large array of biological functions due to its ability to interact with various proteins and ion channels. Crystal structures of human S1R revealed the trimeric organization for which each protomer comprises the ligand binding pocket. This study applied a multistep computational procedure to develop a pharmacophore model obtained from molecular dynamics simulations of available cocrystal structures of well-known S1R ligands. Apart from the well-established positive ionizable and hydrophobic features, the obtained model included an additional specific hydrophobic feature and different excluded volumes, thus increasing the selectivity of the model as well as a more detailed determination of the distance between two essential features. The obtained pharmacophore model passed the validation test by receiver operating characteristic (ROC) curve analysis of active and inactive S1R ligands. Finally, the pharmacophoric performance was experimentally investigated through the synthesis and binding assay of new 4-phenylpiperazine-based compounds. The most active new ligand 2-(3-methyl-1-piperidyl)-1-(4-phenylpiperazin-1-yl)ethanone ( 3 ) showed an S1R affinity close to the reference compound haloperidol ( K
i values of 4.8 and 2.6 nM, respectively). The proposed pharmacophore model can represent a useful tool to design and discover new potent S1R ligands.- Published
- 2024
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8. MAATrica: a measure for assessing consistency and methods in medicinal and nutraceutical chemistry papers.
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Panzarella G, Gallo A, Coecke S, Querci M, Ortuso F, Hofmann-Apitius M, Veltri P, Bajorath J, and Alcaro S
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- Chemistry, Pharmaceutical, Humans, Semantics, Dietary Supplements analysis
- Abstract
The growing number of scientific papers and document sources underscores the need for methods capable of evaluating the quality of publications. Researchers who are looking for relevant papers for their studies need ways to assess the scientific value of these documents. One approach involves using semantic search engines that can automatically extract important knowledge from the growing body of text. In this study, we introduce a new metric called "MAATrica," which serves as the foundation for an innovative method designed to evaluate research papers. MAATrica offers a new way to analyze and categorize text, focusing on the consistency of research documents in the life sciences, particularly in the fields of medicinal and nutraceutical chemistry. This method utilizes semantic descriptions to cover in silico experiments, as well as in vitro and in vivo essays. Created to aid in evaluation processes like peer review, MAATrica uses toolkits and semantic applications to build the proposed measure, identify scientific entities, and gather information. We have applied MAATrica to roughly 90,000 papers and present our findings here., Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: GIULIA PANZARELLA reports financial support was provided by Magna Graecia University of Catanzaro Health Sciences Department. GIULIA PANZARELLA reports financial support was provided by DAAD - German Academic Exchange Service. If there are other authors, they declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Authors. Published by Elsevier Masson SAS.. All rights reserved.)
- Published
- 2024
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9. A Dynamic and Effective Peptide-Based Strategy for Promptly Addressing Emerging SARS-CoV-2 Variants of Concern.
- Author
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Murdocca M, Romeo I, Citro G, Latini A, Centofanti F, Bugatti A, Caccuri F, Caruso A, Ortuso F, Alcaro S, Sangiuolo F, and Novelli G
- Abstract
Genomic surveillance based on sequencing the entire genetic code of SARS-CoV-2 involves monitoring and studying genetic changes and variations in disease-causing organisms such as viruses and bacteria. By tracing the virus, it is possible to prevent epidemic spread in the community, ensuring a 'precision public health' strategy. A peptide-based design was applied to provide an efficacious strategy that is able to counteract any emerging viral variant of concern dynamically and promptly to affect the outcomes of a pandemic at an early stage while waiting for the production of the anti-variant-specific vaccine, which require longer times. The inhibition of the interaction between the receptor-binding domain (RBD) of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and one of the cellular receptors (DPP4) that its receptors routinely bind to infect human cells is an intriguing therapeutic approach to prevent the virus from entering human cells. Among the other modalities developed for this purpose, peptides surely offer unique advantages, including ease of synthesis, serum stability, low immunogenicity and toxicity, and small production and distribution chain costs. Here, we obtained a potent new inhibitor based on the rearrangement of a previously identified peptide that has been rationally designed on a cell dipeptidyl peptidase 4 (DPP4) sequence, a ubiquitous membrane protein known to bind the RBD-SPIKE domain of the virus. This novel peptide (named DPP4-derived ), conceived as an endogenous "drug", is capable of targeting the latest tested variants with a high affinity, reducing the VSV* DG-Fluc pseudovirus Omicron's infection capacity by up to 14%, as revealed by in vitro testing in human Calu-3 cells. Surface plasmon resonance (SPR) confirmed the binding affinity of the new DPP4-derived peptide with Omicron variant RBD.
- Published
- 2024
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10. 8-Amide and 8-carbamate substitution patterns as modulators of 7-hydroxy-4-methylcoumarin's antidepressant profile: Synthesis, biological evaluation and docking studies.
- Author
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Matos MJ, Novo P, Mayán L, Torres I, Uriarte E, Yáñez M, Fontenla JÁ, Ortuso F, Alcaro S, Procopio F, Rodríguez-Franco MI, Val C, Loza MI, Brea J, Borges F, and Viña D
- Subjects
- Humans, Molecular Docking Simulation, Monoamine Oxidase metabolism, Antidepressive Agents pharmacology, Structure-Activity Relationship, Monoamine Oxidase Inhibitors chemistry, Carbamates pharmacology
- Abstract
Psychiatric and neurological disorders affect millions of people worldwide. Currently available treatments may help to improve symptoms, but they cannot cure the diseases. Therefore, there is an urgent need for potent and safe therapeutic solutions. 8-Amide and 8-carbamatecoumarins were synthetized and evaluated as human monoamine oxidase A and B (hMAO-A and hMAO-B) inhibitors. Comparison between both scaffolds has been established, and we hypothesized that the introduction of different substituents can modulate hMAO activity and selectivity. N-(7-Hydroxy-4-methylcoumarin-8-yl)-4-methylbenzamide (9) and ethyl N-(7-hydroxy-4-methylcoumarin-8-yl)carbamate (20) proved to be the most active and selective hMAO-A inhibitors (IC
50 = 15.0 nM and IC50 = 22.0 nM, respectively), being compound 9 an irreversible hMAO-A inhibitor twenty-four times more active in vitro than moclobemide, a drug used in the treatment of depression and anxiety. Based on PAMPA assay results, both compounds proved to be good candidates to cross the blood-brain barrier. In addition, these compounds showed non-significant cytotoxicity on neuronal viability assays. Also, the best compound proved to have a t1/2 of 6.84 min, an intrinsic clearance of 195.63 μL min-1 mg-1 protein, and to be chemically stable at pH 3.0, 7.4 and 10.0. Docking studies were performed to better understand the binding affinities and selectivity profiles for both hMAO isoforms. Finally, theoretical drug-like properties calculations corroborate the potential of both scaffolds on the search for new therapeutic solutions for psychiatric disorders as depression., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 The Authors. Published by Elsevier Masson SAS.. All rights reserved.)- Published
- 2023
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11. Ferritin Heavy Chain Binds Peroxiredoxin 6 and Inhibits Cell Proliferation and Migration.
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Di Sanzo M, Cozzolino F, Battaglia AM, Aversa I, Monaco V, Sacco A, Biamonte F, Palmieri C, Procopio F, Santamaria G, Ortuso F, Pucci P, Monti M, and Faniello MC
- Subjects
- Humans, HEK293 Cells, Cell Proliferation, Iron metabolism, Apoferritins genetics, Peroxiredoxin VI metabolism
- Abstract
The H Ferritin subunit (FTH1), as well as regulating the homeostasis of intracellular iron, is involved in complex pathways that might promote or inhibit carcinogenesis. This function may be mediated by its ability to interact with different molecules. To gain insight into the FTH1 interacting molecules, we analyzed its interactome in HEK293T cells. Fifty-one proteins have been identified, and among them, we focused our attention on a member of the peroxiredoxin family (PRDX6), an antioxidant enzyme that plays an important role in cell proliferation and in malignancy development. The FTH1/PRDX6 interaction was further supported by co-immunoprecipitation, in HEK293T and H460 cell lines and by means of computational methods. Next, we demonstrated that FTH1 could inhibit PRDX6-mediated proliferation and migration. Then, the results so far obtained suggested that the interaction between FTH1/PRDX6 in cancer cells might alter cell proliferation and migration, leading to a less invasive phenotype.
- Published
- 2022
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12. Design and synthesis of chromone-based monoamine oxidase B inhibitors with improved drug-like properties.
- Author
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Reis J, Fernandes C, Salem H, Maia M, Tomé C, Benfeito S, Teixeira J, Oliveira PJ, Uriarte E, Ortuso F, Alcaro S, Bagetta D, Cagide F, and Borges F
- Subjects
- Benzopyrans, Dopamine Agents pharmacology, Ferric Compounds, Humans, Monoamine Oxidase metabolism, Structure-Activity Relationship, Chromones chemistry, Monoamine Oxidase Inhibitors chemistry
- Abstract
The absence of disease modifying drugs in Parkinson's disease therapy urges for new chemical entities acting on relevant PD-associated biological targets. As a result, developing selective and reversible inhibitors targeting MAO-B is still a desirable line of therapeutic research. Within this framework, a small library of chromone derivatives was synthesized and screened towards human monoamine oxidases. Structural modifications on the chromone 3-phenylcarboxamide resulted in potent MAO-B inhibitors with an improved drug-like profile, and for the first time we obtained potent and selective chromone 2-phenylcarboxamides acting in the low nanomolar range. Compounds 5-hydroxy-4-oxo-N-phenyl-4H-chromene-3-carboxamide (38) (IC
50 = 13.0 nM) and N-(4-chlorophenyl)-5-hydroxy-4-oxo-4H-chromene-3-carboxamide (41) (IC50 = 8.3 nM) stood out as reversible, potent, selective and non-cytotoxic MAO-B inhibitors bearing a favourable drug-like profile. Both compounds displayed cytoprotective effects towards iron(III) oxidative stressor., (Copyright © 2022 Elsevier Masson SAS. All rights reserved.)- Published
- 2022
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13. Structural genetics of circulating variants affecting the SARS-CoV-2 spike/human ACE2 complex.
- Author
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Ortuso F, Mercatelli D, Guzzi PH, and Giorgi FM
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- Angiotensin-Converting Enzyme 2 metabolism, COVID-19 genetics, COVID-19 virology, Humans, Mutation, Peptidyl-Dipeptidase A chemistry, Protein Binding, Spike Glycoprotein, Coronavirus metabolism, Angiotensin-Converting Enzyme 2 chemistry, Angiotensin-Converting Enzyme 2 genetics, SARS-CoV-2 chemistry, SARS-CoV-2 genetics, SARS-CoV-2 metabolism, Spike Glycoprotein, Coronavirus chemistry, Spike Glycoprotein, Coronavirus genetics
- Abstract
SARS-CoV-2 entry in human cells is mediated by the interaction between the viral Spike protein and the human ACE2 receptor. This mechanism evolved from the ancestor bat coronavirus and is currently one of the main targets for antiviral strategies. However, there currently exist several Spike protein variants in the SARS-CoV-2 population as the result of mutations, and it is unclear if these variants may exert a specific effect on the affinity with ACE2 which, in turn, is also characterized by multiple alleles in the human population. In the current study, the GBPM analysis, originally developed for highlighting host-guest interaction features, has been applied to define the key amino acids responsible for the Spike/ACE2 molecular recognition, using four different crystallographic structures. Then, we intersected these structural results with the current mutational status, based on more than 295,000 sequenced cases, in the SARS-CoV-2 population. We identified several Spike mutations interacting with ACE2 and mutated in at least 20 distinct patients: S477N, N439K, N501Y, Y453F, E484K, K417N, S477I and G476S. Among these, mutation N501Y in particular is one of the events characterizing SARS-CoV-2 lineage B.1.1.7, which has recently risen in frequency in Europe. We also identified five ACE2 rare variants that may affect interaction with Spike and susceptibility to infection: S19P, E37K, M82I, E329G and G352V.Communicated by Ramaswamy H. Sarma.
- Published
- 2022
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14. Identification of SET/EED dual binders as innovative PRC2 inhibitors.
- Author
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Catalano R, Maruca A, Rocca R, Tassone P, Panzarella G, Costa G, Ortuso F, and Alcaro S
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- Catalytic Domain, Histones metabolism, Ligands, Neoplasms drug therapy, Polycomb Repressive Complex 2 chemistry, Polycomb Repressive Complex 2 metabolism
- Abstract
Background: The inhibition of PRC2, implicated in the pathogenesis of several tumors, can be a useful therapeutic strategy for cancer treatment. In the literature, two types of PRC2 modulators are reported: competitive inhibitors of S-adenosyl methionine binding to the catalytic subunit EZH2; and allosteric ligands that prevent the interaction of the trimethylated H3K27 lysine in histone 3 to the EED subunit. The lack of dual EZH2/EED modulators drove us to search for compounds capable of recognizing both domains. Materials & methods: This goal was pursued by combining pharmacophore- and docking-based virtual screening of the Multi-Target Ligand Chemotheca database. Prediction tools for absorption, distribution, metabolism and excretion and pan-assay interference compounds were also applied. Results: Finally, five 1,2,3-triazole derivatives were identified as promising dual EZH2/EED modulators. Conclusion: Our multistage screening protocol highlighted the great potential of Chemotheca for identifying polypharmacological agents.
- Published
- 2022
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15. Chromene Derivatives as Selective TERRA G-Quadruplex RNA Binders with Antiproliferative Properties.
- Author
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Rocca R, Scionti F, Nadai M, Moraca F, Maruca A, Costa G, Catalano R, Juli G, Di Martino MT, Ortuso F, Alcaro S, Tagliaferri P, Tassone P, Richter SN, and Artese A
- Abstract
In mammalian cells, telomerase transcribes telomeres in large G-rich non-coding RNA, known as telomeric repeat-containing RNA (TERRA), which folds into noncanonical nucleic acid secondary structures called G-quadruplexes (G4s). Since TERRA G4 has been shown to be involved in telomere length and translation regulation, it could provide valuable insight into fundamental biological processes, such as cancer growth, and TERRA G4 binders could represent an innovative strategy for cancer treatment. In this work, the three best candidates identified in our previous virtual screening campaign on bimolecular DNA/RNA G4s were investigated on the monomolecular Tel DNA and TERRA G4s by means of molecular modelling simulations and in vitro and in cell analysis. The results obtained in this work highlighted the stabilizing power of all the three candidates on TERRA G4. In particular, the two compounds characterized by a chromene scaffold were selective TERRA G4 binders, while the compound with a naphthyridine core acted as a dual Tel/TERRA G4-binder. A biophysical investigation by circular dichroism confirmed the relative stabilization efficiency of the compounds towards TERRA and Tel G4s. The TERRA G4 stabilizing hits showed good antiproliferative activity against colorectal and lung adenocarcinoma cell lines. Lead optimization to increase TERRA G4 stabilization may provide new powerful tools against cancer.
- Published
- 2022
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16. Molecular Modeling and Experimental Evaluation of Non-Chiral Components of Bergamot Essential Oil with Inhibitory Activity against Human Monoamine Oxidases.
- Author
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Catalano R, Procopio F, Chavarria D, Benfeito S, Alcaro S, Borges F, and Ortuso F
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- Humans, Molecular Docking Simulation, Molecular Dynamics Simulation, Molecular Structure, Monoamine Oxidase metabolism, Monoamine Oxidase Inhibitors chemistry, Monoamine Oxidase Inhibitors pharmacology, Structure-Activity Relationship, Monarda, Oils, Volatile pharmacology
- Abstract
Human monoamine oxidases ( h MAOs) are well-established targets for the treatment of neurological disorders such as depression, Parkinson's disease and Alzheimer's disease. Despite the efforts carried out over the years, few selective and reversible MAO inhibitors are on the market. Thus, a continuous search for new compounds is needed. Herein, MAO inhibitors were searched among the non-chiral constituents of Bergamot Essential Oil (BEO) with the aid of computational tools. Accordingly, molecular modeling simulations were carried out on both h MAO-A and h MAO-B for the selected constituents. The theoretically predicted target recognition was then used to select the most promising compounds. Among the screened compounds, Bergamottin, a furocoumarin, showed selective h MAO-B inhibitory activity, fitting its active site well. Molecular dynamics simulations were used to deeply analyze the target recognition and to rationalize the selectivity preference. In agreement with the computational results, experimental studies confirmed both the h MAO inhibition properties of Bergamottin and its preference for the isoform B.
- Published
- 2022
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17. Selective inhibition of carbonic anhydrase IX and XII by coumarin and psoralen derivatives.
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Meleddu R, Deplano S, Maccioni E, Ortuso F, Cottiglia F, Secci D, Onali A, Sanna E, Angeli A, Angius R, Alcaro S, Supuran CT, and Distinto S
- Subjects
- Antigens, Neoplasm metabolism, Carbonic Anhydrase IX metabolism, Carbonic Anhydrase Inhibitors chemical synthesis, Carbonic Anhydrase Inhibitors chemistry, Coumarins chemical synthesis, Coumarins chemistry, Dose-Response Relationship, Drug, Ficusin chemical synthesis, Ficusin chemistry, Humans, Models, Molecular, Molecular Structure, Structure-Activity Relationship, Carbonic Anhydrase IX antagonists & inhibitors, Carbonic Anhydrase Inhibitors pharmacology, Carbonic Anhydrases metabolism, Coumarins pharmacology, Ficusin pharmacology
- Abstract
A small library of coumarin and their psoralen analogues EMAC10157a-b-d-g and EMAC10160a-b-d-g has been designed and synthesised to investigate the effect of structural modifications on their inhibition ability and selectivity profile towards carbonic anhydrase isoforms I, II, IX, and XII. None of the new compounds exhibited activity towards hCA I and II isozymes. Conversely, both coumarin and psoralen derivatives were active against tumour associated isoforms IX and XII in the low micromolar or nanomolar range of concentration. These data further corroborate our previous findings on analogous derivatives, confirming that both coumarins and psoralens are interesting scaffolds for the design of isozyme selective hCA inhibitors.
- Published
- 2021
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18. Exploring New Scaffolds for the Dual Inhibition of HIV-1 RT Polymerase and Ribonuclease Associated Functions.
- Author
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Meleddu R, Corona A, Distinto S, Cottiglia F, Deplano S, Sequeira L, Secci D, Onali A, Sanna E, Esposito F, Cirone I, Ortuso F, Alcaro S, Tramontano E, Mátyus P, and Maccioni E
- Subjects
- Anti-HIV Agents pharmacology, HIV Reverse Transcriptase chemistry, HIV-1 enzymology, Inhibitory Concentration 50, Ligands, Molecular Docking Simulation, Small Molecule Libraries, Structure-Activity Relationship, Thiazoles chemical synthesis, Anti-HIV Agents chemistry, HIV Reverse Transcriptase antagonists & inhibitors, HIV-1 metabolism, Ribonuclease H antagonists & inhibitors, Thiazoles chemistry, Thiazoles pharmacology
- Abstract
Current therapeutic protocols for the treatment of HIV infection consist of the combination of diverse anti-retroviral drugs in order to reduce the selection of resistant mutants and to allow for the use of lower doses of each single agent to reduce toxicity. However, avoiding drugs interactions and patient compliance are issues not fully accomplished so far. Pursuing on our investigation on potential anti HIV multi-target agents we have designed and synthesized a small library of biphenylhydrazo 4-arylthiazoles derivatives and evaluated to investigate the ability of the new derivatives to simultaneously inhibit both associated functions of HIV reverse transcriptase. All compounds were active towards the two functions, although at different concentrations. The substitution pattern on the biphenyl moiety appears relevant to determine the activity. In particular, compound 2-{3-[(2-{4-[4-(hydroxynitroso)phenyl]-1,3-thiazol-2-yl} hydrazin-1-ylidene) methyl]-4-methoxyphenyl} benzamide bromide ( EMAC2063 ) was the most potent towards RNaseH (IC
50 = 4.5 mM)- and RDDP (IC50 = 8.0 mM) HIV RT-associated functions.- Published
- 2021
- Full Text
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19. From Homology Modeling to the Hit Identification and Drug Repurposing: A Structure-Based Approach in the Discovery of Novel Potential Anti-Obesity Compounds.
- Author
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Costa G, Artese A, Ortuso F, and Alcaro S
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- Drug Design, In Vitro Techniques, Ligands, Models, Chemical, Molecular Dynamics Simulation, Molecular Structure, Small Molecule Libraries, Software, Structure-Activity Relationship, Anti-Obesity Agents chemistry, Carbonic Anhydrase Inhibitors chemistry, Drug Repositioning methods, Molecular Docking Simulation methods
- Abstract
Although science and technology have progressed rapidly, de novo drug development has been a costly and time-consuming process over the past decades. In this scenario, drug repurposing has appeared as an alternative tool to accelerate the drug development process. Herein, we applied such an approach to the highly popular human Carbonic Anhydrase (hCA) VA drug target, that is involved in ureagenesis, gluconeogenesis, lipogenesis, and in the metabolism regulation. Albeit several hCA inhibitors have been designed and are currently in clinical use, serious drug interactions have been reported due to their poor selectivity. In this perspective, the drug repurposing approach could be a useful tool for investigating the drug promiscuity/polypharmacology profile. In this chapter, we describe a combination of virtual screening techniques and in vitro assays aimed to identify novel selective hCA VA inhibitors and to repurpose drugs known for other clinical indications.
- Published
- 2021
- Full Text
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20. Natural Products Extracted from Fungal Species as New Potential Anti-Cancer Drugs: A Structure-Based Drug Repurposing Approach Targeting HDAC7.
- Author
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Maruca A, Rocca R, Catalano R, Mesiti F, Costa G, Lanzillotta D, Salatino A, Ortuso F, Trapasso F, Alcaro S, and Artese A
- Subjects
- Antineoplastic Agents isolation & purification, Binding Sites, Biological Products isolation & purification, Cell Line, Tumor, Drug Repositioning, Histone Deacetylase Inhibitors isolation & purification, Histone Deacetylases, Humans, Molecular Docking Simulation, Molecular Dynamics Simulation, Molecular Structure, Protein Binding, Structure-Activity Relationship, Antineoplastic Agents chemistry, Antineoplastic Agents pharmacology, Biological Products chemistry, Biological Products pharmacology, Fungi chemistry, Histone Deacetylase Inhibitors chemistry, Histone Deacetylase Inhibitors pharmacology
- Abstract
Mushrooms can be considered a valuable source of natural bioactive compounds with potential polypharmacological effects due to their proven antimicrobial, antiviral, antitumor, and antioxidant activities. In order to identify new potential anticancer compounds, an in-house chemical database of molecules extracted from both edible and non-edible fungal species was employed in a virtual screening against the isoform 7 of the Histone deacetylase (HDAC). This target is known to be implicated in different cancer processes, and in particular in both breast and ovarian tumors. In this work, we proposed the ibotenic acid as lead compound for the development of novel HDAC7 inhibitors, due to its antiproliferative activity in human breast cancer cells (MCF-7). These promising results represent the starting point for the discovery and the optimization of new HDAC7 inhibitors and highlight the interesting opportunity to apply the "drug repositioning" paradigm also to natural compounds deriving from mushrooms.
- Published
- 2020
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21. Multi-Targeting Bioactive Compounds Extracted from Essential Oils as Kinase Inhibitors.
- Author
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Maruca A, Lanzillotta D, Rocca R, Lupia A, Costa G, Catalano R, Moraca F, Gaudio E, Ortuso F, Artese A, Trapasso F, and Alcaro S
- Subjects
- Cell Line, Tumor, Cell Survival drug effects, Cinnamates pharmacology, ErbB Receptors chemistry, Humans, Ligands, Molecular Docking Simulation, Oils, Volatile analysis, Polypharmacology, Protein-Tyrosine Kinases chemistry, Proto-Oncogene Proteins B-raf chemistry, Pyruvate Dehydrogenase Acetyl-Transferring Kinase chemistry, Receptor Protein-Tyrosine Kinases chemistry, Structure-Activity Relationship, Antineoplastic Agents pharmacology, Oils, Volatile chemistry, Protein Kinase Inhibitors pharmacology, Protein Kinases chemistry
- Abstract
Essential oils (EOs) are popular in aromatherapy, a branch of alternative medicine that claims their curative effects. Moreover, several studies reported EOs as potential anti-cancer agents by inducing apoptosis in different cancer cell models. In this study, we have considered EOs as a potential resource of new kinase inhibitors with a polypharmacological profile. On the other hand, computational methods offer the possibility to predict the theoretical activity profile of ligands, discovering dangerous off-targets and/or synergistic effects due to the potential multi-target action. With this aim, we performed a Structure-Based Virtual Screening (SBVS) against X-ray models of several protein kinases selected from the Protein Data Bank (PDB) by using a chemoinformatics database of EOs. By evaluating theoretical binding affinity, 13 molecules were detected among EOs as new potential kinase inhibitors with a multi-target profile. The two compounds with higher percentages in the EOs were studied more in depth by means Induced Fit Docking (IFD) protocol, in order to better predict their binding modes taking into account also structural changes in the receptor. Finally, given its good binding affinity towards five different kinases, cinnamyl cinnamate was biologically tested on different cell lines with the aim to verify the antiproliferative activity. Thus, this work represents a starting point for the optimization of the most promising EOs structure as kinase inhibitors with multi-target features.
- Published
- 2020
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22. Multi-target drug discovery: An opportunity for novel and repurposed bioactive compounds.
- Author
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Alcaro S and Ortuso F
- Subjects
- Anniversaries and Special Events, Chemistry, Pharmaceutical economics, Chemistry, Pharmaceutical organization & administration, History, 20th Century, History, 21st Century, Italy, Chemistry, Pharmaceutical history, Drug Discovery, Drug Repositioning
- Published
- 2020
- Full Text
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23. Folding intermediate states of the parallel human telomeric G-quadruplex DNA explored using Well-Tempered Metadynamics.
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Rocca R, Palazzesi F, Amato J, Costa G, Ortuso F, Pagano B, Randazzo A, Novellino E, Alcaro S, Moraca F, and Artese A
- Subjects
- Humans, Imaging, Three-Dimensional, Thermodynamics, DNA chemistry, G-Quadruplexes, Molecular Dynamics Simulation, Telomere chemistry
- Abstract
An increasingly comprehension of the folding intermediate states of DNA G-quadruplexes (G4s) is currently an important scientific challenge, especially for the human telomeric (h-tel) G4s-forming sequences, characterized by a highly polymorphic nature. Despite the G-triplex conformation was proposed as one of the possible folding intermediates for the antiparallel and hybrid h-tel G4s, for the parallel h-tel topology with an all-anti guanine orientation, a vertical strand-slippage involving the G-triplets was proposed in previous works through microseconds-long standard molecular dynamics simulations (MDs). Here, in order to get further insights into the vertical strand-slippage and the folding intermediate states of the parallel h-tel G4s, we have carried out a Well-Tempered Metadynamics simulation (WT-MetaD), which allowed us to retrieve an ensemble of six G4s having two/G-tetrad conformations derived by the G-triplets vertical slippage. The insights highlighted in this work are aimed at rationalizing the mechanistic characterisation of the parallel h-tel G4 folding process.
- Published
- 2020
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24. New Dihydrothiazole Benzensulfonamides: Looking for Selectivity toward Carbonic Anhydrase Isoforms I, II, IX, and XII.
- Author
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Meleddu R, Distinto S, Cottiglia F, Angius R, Caboni P, Angeli A, Melis C, Deplano S, Alcaro S, Ortuso F, Supuran CT, and Maccioni E
- Abstract
In the present study we investigated the structure-activity relationships of a new series of 4-[(3-ethyl-4-aryl-2,3-dihydro-1,3-thiazol-2-ylidene)amino]benzene-1-sulfonamides ( EMAC10101a - m ). All synthesized compounds, with the exception of compound EMAC10101k , preferentially inhibit off-target hCA II isoform. Within the series, compound EMAC10101d , bearing a 2,4-dichorophenyl substituent in position 4 of the dihydrothiazole ring, was the most potent and selective toward hCA II with an inhibitory activity in the low nanomolar range., Competing Interests: The authors declare no competing financial interest., (Copyright © 2020 American Chemical Society.)
- Published
- 2020
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25. BOPC1 Enantiomers Preparation and HuR Interaction Study. From Molecular Modeling to a Curious DEEP-STD NMR Application.
- Author
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Volpe SD, Listro R, Parafioriti M, Di Giacomo M, Rossi D, Ambrosio FA, Costa G, Alcaro S, Ortuso F, Hirsch AKH, Vasile F, and Collina S
- Abstract
The Hu family of RNA-binding proteins plays a crucial role in post-transcriptional processes; indeed, Hu-RNA complexes are involved in various dysfunctions (i.e., inflammation, neurodegeneration, and cancer) and have been recently proposed as promising therapeutic targets. Intrigued by this concept, our research efforts aim at identifying small molecules able to modulate HuR-RNA interactions, with a focus on subtype HuR, upregulated and dysregulated in several cancers. By applying structure-based design, we had already identified racemic trans - BOPC1 as promising HuR binder. In this Letter, we accomplished the enantio-resolution, the assignment of the absolute configuration, and the recognition study with HuR of enantiomerically pure trans - BOPC1 . For the first time, we apply DEEP (differential epitope mapping)-STD NMR to study the interaction of BOPC1 with HuR and compare its enantiomers, gaining information on ligand orientation and amino acids involved in the interaction, and thus increasing focus on the in silico binding site model., Competing Interests: The authors declare no competing financial interest., (Copyright © 2020 American Chemical Society.)
- Published
- 2020
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26. Mediterranean products as promising source of multi-target agents in the treatment of metabolic syndrome.
- Author
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Bagetta D, Maruca A, Lupia A, Mesiti F, Catalano R, Romeo I, Moraca F, Ambrosio FA, Costa G, Artese A, Ortuso F, Alcaro S, and Rocca R
- Subjects
- Anti-Inflammatory Agents, Non-Steroidal chemistry, Antioxidants chemistry, Dose-Response Relationship, Drug, Humans, Metabolic Syndrome metabolism, Molecular Structure, Phytochemicals chemistry, Protective Agents chemistry, Structure-Activity Relationship, Anti-Inflammatory Agents, Non-Steroidal therapeutic use, Antioxidants therapeutic use, Diet, Mediterranean, Metabolic Syndrome drug therapy, Phytochemicals therapeutic use, Protective Agents therapeutic use
- Abstract
Alteration of nutritional habits play an essential role on the risk of developing Metabolic Syndrome (MetS). Several epidemiological studies have shown that assuming diets rich of foods included in the Mediterranean diet (MetDiet) pattern like, such as olive oil, nuts, fruit, fiber, vegetables, wine and grain cereals has protective effects on the different risk factors characterizing the MetS. The beneficial effects of the MetDiet in the MetS are mainly due to the antioxidant and anti-inflammatory properties of the most abundant phytochemical components of such foods as polyphenols like resveratrol and oleuropein, allyl sulfides, ellagic acid, mono- and poly-unsaturated fatty acids (MUFA and PUFA), tocopherols and flavonoids like quercetin, which have shown positive results in the prevention of cardiovascular diseases (CVDs), with related risk factors, like hypertension, hypercholesterolemia and obesity. In this review, we highlighted the multi-target activities of the bioactive components contained in some foods typical of the Mediterranean area like olive oil, onion, liquorice, rosemary, oregano, hazelnut, pistachio, "Melannurca" apple, red wine, hot pepper, Citrus sp. fruits, saffron and garlic, with particular focus on their impact on health outcomes in relation to MetS main key factors, such as insulin resistance (IR) and type 2 diabetes mellitus (T2DM), endothelial dysfunctions, inflammatory response, oxidative stress and dyslipidaemic and hypercholesterolemic effects., (Copyright © 2019 Elsevier Masson SAS. All rights reserved.)
- Published
- 2020
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27. Molecular modelling of epitopes recognized by neoplastic B lymphocytes in Chronic Lymphocytic Leukemia.
- Author
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Lupia A, Mimmi S, Iaccino E, Maisano D, Moraca F, Talarico C, Vecchio E, Fiume G, Ortuso F, Scala G, Quinto I, and Alcaro S
- Subjects
- Antineoplastic Agents chemistry, Dose-Response Relationship, Drug, Drug Screening Assays, Antitumor, Humans, Models, Molecular, Molecular Structure, Peptides chemistry, Quantitative Structure-Activity Relationship, Antineoplastic Agents pharmacology, B-Lymphocytes drug effects, Epitopes analysis, Leukemia, Lymphocytic, Chronic, B-Cell drug therapy, Peptides pharmacology
- Abstract
Identification of epitopes recognized by tumour B cells could provide insights into the molecular mechanisms of B cell tumorigenesis through aberrant B cell receptor (BCR) signalling. Here, we analysed the structure of eleven peptides binders of BCRs expressed in Chronic Lymphocytic Leukemia (CLL) patients in order to identify the chemical features required for cross-reactive binding to different CLL clonotypes. Four cross-reactive (CR) and seven no-cross-reactive (NCR) peptides were analysed by means of GRID molecular interaction fields, ligand-based pharmacophore and 3D-QSAR approaches. Based on pharmacophore model, two peptides were generated by specific amino acids substitutions of the parental NCR peptides; these new peptides resumed the common chemical features of CR peptides and bound the CLL BCR clonotypes recognized by CR peptides and parental NCR peptides. Thus, our computational approach guided the pharmacophore modelling of CR peptides. In perspective, peptide binders of CLL BCR clonotypes could represent a powerful tool for computational modelling of epitopes recognized by tumour B cells clones., (Copyright © 2019 Elsevier Masson SAS. All rights reserved.)
- Published
- 2020
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28. Review about the multi-target profile of resveratrol and its implication in the SGK1 inhibition.
- Author
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Catalogna G, Moraca F, D'Antona L, Dattilo V, Perrotti G, Lupia A, Costa G, Ortuso F, Iuliano R, Trapasso F, Amato R, Alcaro S, and Perrotti N
- Subjects
- Animals, Anti-Inflammatory Agents pharmacology, Antioxidants pharmacology, Cardiotonic Agents pharmacology, Cell Line, Tumor, Cell Survival drug effects, Humans, Hypoglycemic Agents pharmacology, Molecular Targeted Therapy, Neuroprotective Agents pharmacology, Antineoplastic Agents pharmacology, Immediate-Early Proteins antagonists & inhibitors, Protein Serine-Threonine Kinases antagonists & inhibitors, Resveratrol pharmacology
- Abstract
Resveratrol (trans-3,4',5-trihydroxystilbene) is a polyphenolic natural product with a well-known polypharmacological profile that places it among the multi-target-directed ligands (MTDLs). Given its protective action against a wide number of chronic diseases, in this review, we introduce a general overview about the cardioprotective and antioxidant effects, the antidiabetic, neuroprotective and anti-inflammatory effects of this polyphenol. In the second part of the manuscript, we focused our attention on the anticancer activity of Resveratrol, given the alteration of many different signaling pathways, leading to suppression of tumor cell proliferation in numerous cancer types. Among the several anticancer targets involved in the mechanism of action of Resveratrol, here we introduce experimental and molecular modeling studies performed against the SGK1 protein as a novel anticancer target of Resveratrol. SGK1 inhibitors have been demonstrated to inhibit cell growth of different cancer cells. We demonstrated that resveratrol inhibits SGK1 in vitro and in intact cells, affecting proliferation and survival of HUH7 human hepatoma cells. Our findings demonstrate that resveratrol may function as a SGK1 inhibitor, suggesting possible applications in sodium retention and cancer., (Copyright © 2019 Elsevier Masson SAS. All rights reserved.)
- Published
- 2019
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29. Exploring new structural features of the 4-[(3-methyl-4-aryl-2,3-dihydro-1,3-thiazol-2-ylidene)amino]benzenesulphonamide scaffold for the inhibition of human carbonic anhydrases.
- Author
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Distinto S, Meleddu R, Ortuso F, Cottiglia F, Deplano S, Sequeira L, Melis C, Fois B, Angeli A, Capasso C, Angius R, Alcaro S, Supuran CT, and Maccioni E
- Subjects
- Carbonic Anhydrase Inhibitors chemical synthesis, Carbonic Anhydrase Inhibitors chemistry, Dose-Response Relationship, Drug, Humans, Isoenzymes antagonists & inhibitors, Isoenzymes metabolism, Models, Molecular, Molecular Structure, Structure-Activity Relationship, Carbonic Anhydrase Inhibitors pharmacology, Carbonic Anhydrases metabolism
- Abstract
A library of 4-[(3-methyl-4-aryl-2,3-dihydro-1,3-thiazol-2-ylidene)amino]benzene-1-sulphonamides ( EMAC8002a-m ) was designed and synthesised to evaluate the effect of substituents in the positions 3 and 4 of the dihydrothiazole ring on the inhibitory potency and selectivity toward human carbonic anhydrase isoforms I, II, IX, and XII. Most of the new compounds preferentially inhibit the isoforms II and XII. Both electronic and steric features on the aryl substituent in the position 4 of the dihydrothiazole ring concur to determine the overall biological activity of these new derivatives.
- Published
- 2019
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30. 4-(3-Nitrophenyl)thiazol-2-ylhydrazone derivatives as antioxidants and selective hMAO-B inhibitors: synthesis, biological activity and computational analysis.
- Author
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Secci D, Carradori S, Petzer A, Guglielmi P, D'Ascenzio M, Chimenti P, Bagetta D, Alcaro S, Zengin G, Petzer JP, and Ortuso F
- Subjects
- Acetylcholinesterase metabolism, Antioxidants chemical synthesis, Antioxidants chemistry, Butyrylcholinesterase metabolism, Cholinesterase Inhibitors chemical synthesis, Cholinesterase Inhibitors chemistry, Cholinesterase Inhibitors pharmacology, Humans, Hydrazones chemical synthesis, Hydrazones chemistry, Models, Molecular, Molecular Structure, Monoamine Oxidase Inhibitors chemical synthesis, Monoamine Oxidase Inhibitors chemistry, Thiazoles chemical synthesis, Thiazoles chemistry, Antioxidants pharmacology, Hydrazones pharmacology, Monoamine Oxidase metabolism, Monoamine Oxidase Inhibitors pharmacology, Thiazoles pharmacology
- Abstract
A new series of 4-(3-nitrophenyl)thiazol-2-ylhydrazone derivatives were designed, synthesised, and evaluated to assess their inhibitory effect on the human monoamine oxidase (hMAO) A and B isoforms. Different (un)substituted (hetero)aromatic substituents were linked to N1 of the hydrazone in order to establish robust structure-activity relationships. The results of the biological testing demonstrated that the presence of the hydrazothiazole nucleus bearing at C4 a phenyl ring functionalised at the meta position with a nitro group represents an important pharmacophoric feature to obtain selective and reversible human MAO-B inhibition for the treatment of neurodegenerative disorders. In addition, the most potent and selective MAO-B inhibitors were evaluated in silico as potential cholinesterase (AChE/BuChE) inhibitors and in vitro for antioxidant activities. The results obtained from molecular modelling studies provided insight into the multiple interactions and structural requirements for the reported MAO inhibitory properties.
- Published
- 2019
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31. Benzo[ b ]tiophen-3-ol derivatives as effective inhibitors of human monoamine oxidase: design, synthesis, and biological activity.
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Guglielmi P, Secci D, Petzer A, Bagetta D, Chimenti P, Rotondi G, Ferrante C, Recinella L, Leone S, Alcaro S, Zengin G, Petzer JP, Ortuso F, and Carradori S
- Subjects
- Dose-Response Relationship, Drug, Humans, Models, Molecular, Molecular Structure, Monoamine Oxidase Inhibitors chemical synthesis, Monoamine Oxidase Inhibitors chemistry, Structure-Activity Relationship, Drug Design, Monoamine Oxidase metabolism, Monoamine Oxidase Inhibitors pharmacology
- Abstract
A series of benzo[ b ]thiophen-3-ols were synthesised and investigated as potential human monoamine oxidase (hMAO) inhibitors in vitro as well as ex vivo in rat cortex synaptosomes by means of evaluation of 3,4-dihydroxyphenylacetic acid/dopamine (DOPAC/DA) ratio and lactate dehydrogenase (LDH) activity. Most of these compounds possessed high selectivity for the MAO-B isoform and a discrete antioxidant and chelating potential. Molecular docking studies of all the compounds underscored potential binding site interactions suitable for MAO inhibition activity, and suggested structural requirements to further improve the activity of this scaffold by chemical modification of the aryl substituents. Starting from this heterocyclic nucleus, novel lead compounds for the treatment of neurodegenerative disease could be developed.
- Published
- 2019
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32. A computer-assisted discovery of novel potential anti-obesity compounds as selective carbonic anhydrase VA inhibitors.
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Costa G, Carta F, Ambrosio FA, Artese A, Ortuso F, Moraca F, Rocca R, Romeo I, Lupia A, Maruca A, Bagetta D, Catalano R, Vullo D, Alcaro S, and Supuran CT
- Subjects
- Anti-Obesity Agents chemistry, Carbonic Anhydrase I antagonists & inhibitors, Carbonic Anhydrase I metabolism, Carbonic Anhydrase II antagonists & inhibitors, Carbonic Anhydrase II metabolism, Carbonic Anhydrase Inhibitors chemistry, Computer-Aided Design, Drug Discovery, Humans, Molecular Docking Simulation, Obesity metabolism, Anti-Obesity Agents pharmacology, Carbonic Anhydrase Inhibitors pharmacology, Drug Repositioning, Obesity drug therapy
- Abstract
The human Carbonic anhydrases (hCA) VA and VB play a key role in ureagenesis, gluconeogenesis, lipogenesis and in the metabolism regulation, thus representing highly popular drug targets. Albeit several hCA inhibitors have been designed and are currently in clinical use, serious drug interactions have been reported due to their poor selectivity. In this perspective, the drug repurposing approach could be a useful tool in order to investigate the drug promiscuity/polypharmacology profile. In this study, virtual screening techniques and in vitro assays were combined to identify novel selective hCA VA inhibitors from among around 94000 compounds. The docking analysis highlighted 12 promising best hits, biologically characterized in terms of their hCA VA inhibitory activity. Interestingly, among them, the anticancer agents fludarabine and lenvatinib and the antiepileptic rufinamide were able to selectively inhibit the enzyme activity in the micromolar range, while a pyrido-indole derivative, the homovanillic acid sulfate and the desacetyl metabolite of the antibacterial cephapirin in the nanomolar range., (Copyright © 2019 Elsevier Masson SAS. All rights reserved.)
- Published
- 2019
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33. The Mediterranean Diet as source of bioactive compounds with multi-targeting anti-cancer profile.
- Author
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Maruca A, Catalano R, Bagetta D, Mesiti F, Ambrosio FA, Romeo I, Moraca F, Rocca R, Ortuso F, Artese A, Costa G, Alcaro S, and Lupia A
- Subjects
- Anticarcinogenic Agents analysis, Anticarcinogenic Agents therapeutic use, Antioxidants analysis, Antioxidants therapeutic use, Fruit chemistry, Humans, Neoplasms diet therapy, Olive Oil analysis, Olive Oil therapeutic use, Vegetables chemistry, Wine analysis, Diet, Mediterranean, Neoplasms prevention & control
- Abstract
Many bioactive agents have been extracted from plants or belong to functional foods and have been considered in the treatment of serious and multifactorial diseases, such as cancer. In particular, this review is focused on the anti-cancer properties owned by several natural products typically from the Mediterranean area. In some regions of the South of Italy, a lower cancer incidence has been observed. There is increasing evidence that adherence to a Mediterranean dietary pattern correlates with reduced risk of several cancer types. This could be mainly attributed to the typical lifestyle aspects of the Mediterranean diet, such as high consumption of fruit and vegetables. In this review, the main natural products of the Mediterranean area are discussed, with particular attention on their anti-cancer properties endowed with multi-target profiles., (Copyright © 2019 Elsevier Masson SAS. All rights reserved.)
- Published
- 2019
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34. Benzoic acid-derived nitrones: A new class of potential acetylcholinesterase inhibitors and neuroprotective agents.
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Oliveira C, Bagetta D, Cagide F, Teixeira J, Amorim R, Silva T, Garrido J, Remião F, Uriarte E, Oliveira PJ, Alcaro S, Ortuso F, and Borges F
- Subjects
- Acetylcholinesterase chemistry, Benzamides chemical synthesis, Benzamides chemistry, Benzamides toxicity, Cell Line, Tumor, Cell Survival drug effects, Cholinesterase Inhibitors chemical synthesis, Cholinesterase Inhibitors chemistry, Cholinesterase Inhibitors toxicity, Humans, Imines chemical synthesis, Imines chemistry, Imines toxicity, Kinetics, Molecular Docking Simulation, Molecular Structure, Neuroprotective Agents chemical synthesis, Neuroprotective Agents chemistry, Neuroprotective Agents toxicity, Small Molecule Libraries chemical synthesis, Small Molecule Libraries chemistry, Small Molecule Libraries pharmacology, Small Molecule Libraries toxicity, Structure-Activity Relationship, Acetylcholinesterase metabolism, Benzamides pharmacology, Cholinesterase Inhibitors pharmacology, Imines pharmacology, Neuroprotective Agents pharmacology
- Abstract
The discovery of new chemical entities endowed with potent and selective acetylcholinesterase (AChE) and/or butyrylcholinesterase (BChE) inhibitory activity is still a relevant subject for Alzheimer's disease therapy. Therefore, a small library of benzoic based amide nitrones (compounds 24 to 42) was synthesized and screened toward cholinesterase enzymes. SAR studies showed that the tert-butyl moiety is the most favourable nitrone pattern. In general, tert-butyl derivatives effectively inhibited AChE, being compound 33 the most potent (IC
50 = 8.3 ± 0.3 μM; Ki 5.2 μM). The data pointed to a non-competitive inhibition mechanism of action, which was also observed for the standard donepezil. None of compounds showed BChE inhibitory activity. Molecular modelling studies provided insights into the enzyme-inhibitor interactions and rationalised the experimental data, confirming that the binding mode of nitrones 33 and 38 towards AChE has the most favourable binding free energy. The tert-butylnitrones 33 and 38 were not cytotoxic on different cell lines (SH-SY5Y and HepG2). Moreover, compound 33 was able to prevent t-BHP-induced oxidative stress in SH-SY5Y differentiated cells. Due to its AChE selectivity and promising cytoprotective properties, as well as its appropriate drug-like profile pointing toward blood-brain barrier permeability, compound 33 is proposed as a valid lead for a further optimization step., (Copyright © 2019 The Authors. Published by Elsevier Masson SAS.. All rights reserved.)- Published
- 2019
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35. Novel natural non-nucleoside inhibitors of HIV-1 reverse transcriptase identified by shape- and structure-based virtual screening techniques.
- Author
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Costa G, Rocca R, Corona A, Grandi N, Moraca F, Romeo I, Talarico C, Gagliardi MG, Ambrosio FA, Ortuso F, Alcaro S, Distinto S, Maccioni E, Tramontano E, and Artese A
- Subjects
- Biological Products chemistry, Drug Evaluation, Preclinical, HIV Reverse Transcriptase metabolism, HIV-1 enzymology, Humans, Microbial Sensitivity Tests, Molecular Conformation, Molecular Dynamics Simulation, Reverse Transcriptase Inhibitors chemistry, Biological Products pharmacology, HIV Reverse Transcriptase antagonists & inhibitors, HIV-1 drug effects, Reverse Transcriptase Inhibitors pharmacology
- Abstract
In this work we report a parallel application of both docking- and shape-based virtual screening (VS) methods, followed by Molecular Dynamics simulations (MDs), for discovering new compounds able to inhibit the human immunodeficiency virus type 1 (HIV-1) reverse transcriptase (RT) RNA-dependent DNA polymerase activity. Specifically, we screened more than 143000 natural compounds commercially available in the ZINC database against the best five RT crystallographic models, taking into account the five approved NNRTIs as query compounds. As a result, 20 hit molecules were selected and tested on biochemical assays for the inhibition of the RNA dependent DNA polymerase RT function and, among them, an indoline pyrrolidine (hit1), an indonyl piperazine (hit2) and an indolyl indolinone (hit3) derivatives were identified as novel non-nucleoside RT inhibitors in the low micromolar range., (Copyright © 2018 Elsevier Masson SAS. All rights reserved.)
- Published
- 2019
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36. Multi-target-directed ligands for Alzheimer's disease: Discovery of chromone-based monoamine oxidase/cholinesterase inhibitors.
- Author
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Reis J, Cagide F, Valencia ME, Teixeira J, Bagetta D, Pérez C, Uriarte E, Oliveira PJ, Ortuso F, Alcaro S, Rodríguez-Franco MI, and Borges F
- Subjects
- Alzheimer Disease drug therapy, Alzheimer Disease metabolism, Blood-Brain Barrier metabolism, Cholinesterase Inhibitors pharmacokinetics, Cholinesterases metabolism, Chromones pharmacokinetics, Drug Design, Hep G2 Cells, Humans, Ligands, Molecular Docking Simulation, Molecular Targeted Therapy, Monoamine Oxidase metabolism, Monoamine Oxidase Inhibitors pharmacokinetics, Cholinesterase Inhibitors chemistry, Cholinesterase Inhibitors pharmacology, Chromones chemistry, Chromones pharmacology, Monoamine Oxidase Inhibitors chemistry, Monoamine Oxidase Inhibitors pharmacology
- Abstract
There has been a substantial research effort to design multi-target ligands for the treatment of Alzheimer's disease (AD), an approach that is moved by the knowledge that AD is a complex and multifactorial disease affecting many linked to pathological pathways. Accordingly, we have devoted efforts to develop multi-target ligands based on the chromone scaffold. As a result, a small library of chromone derivatives was synthesized and screened towards human cholinesterases and monoamine oxidases. Compounds 2-(dimethylamino)ethyl (E)-3-(4-oxo-2-(p-methylphenlcarbamoyl)-4H-chromen-6-yl)acrylate (9a) and 2-(dimethylamino)ethyl (E)-3-(4-oxo-3-(phenylcarbamoyl)-4H-chromen-6-yl)acrylate (23a) were identified as the most promising multi-target inhibitors of the series. Compound 9a acted as a potent, selective and bifunctional AChEI (IC
50 = 0.21 μM, Ki = 0.19 μM) and displayed dual hMAO inhibitory activity (hMAO-A IC50 = 0.94 μM, Ki = 0.057 μM and hMAO-B IC50 = 3.81 μM, Ki = 0.48 μM). Compound 23a acted as a selective IMAO-B (IC50 = 0.63 μM, Ki = 0.34 μM) while still displaying hChE inhibitory and bifunctional activity in the low micromolar range. Overall, these two compounds stand out as reversible multi-target inhibitors with favourable permeability, toxicological and drug-like profiles, thus being valid candidates for subsequent optimization and pre-clinical studies., (Copyright © 2018. Published by Elsevier Masson SAS.)- Published
- 2018
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37. Tuning the Dual Inhibition of Carbonic Anhydrase and Cyclooxygenase by Dihydrothiazole Benzensulfonamides.
- Author
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Meleddu R, Distinto S, Cottiglia F, Angius R, Gaspari M, Taverna D, Melis C, Angeli A, Bianco G, Deplano S, Fois B, Del Prete S, Capasso C, Alcaro S, Ortuso F, Yanez M, Supuran CT, and Maccioni E
- Abstract
A novel series of of 4-[(3-phenyl-4-aryl-2,3-dihydro-1,3-thiazol-2-ylidene)amino]benzene-1-sulfonamides ( EMAC10111a-g ) was synthesized and assayed toward both human carbonic anhydrase isozymes I, II, IX, and XII and cyclooxygenase isoforms. The majority of these derivatives preferentially inhibit hCA isoforms II and XII and hCOX-2 isozyme, indicating that 2,3,4-trisubstituted 2,3-dihydrothiazoles are a promising scaffold for the inhibition of hCA isozymes and of hCOX-2 enzyme. The nature of the substituent at the dihydrothiazole ring position 4 influenced the activity and selectivity toward both enzyme families. EMAC10111g resulted as the best performing compound toward both enzyme families and exhibited preferential activity toward hCA XII and hCOX-2 isozymes., Competing Interests: The authors declare no competing financial interest.
- Published
- 2018
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38. In Silico Identification of Piperidinyl-amine Derivatives as Novel Dual Binders of Oncogene c-myc/c-Kit G-quadruplexes.
- Author
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Rocca R, Moraca F, Costa G, Talarico C, Ortuso F, Da Ros S, Nicoletto G, Sissi C, Alcaro S, and Artese A
- Abstract
In the last years, it has been shown that the DNA secondary structure known as G-quadruplex is also involved in the regulation of oncogenes transcription, such as c-myc , c-Kit , KRAS , Bcl-2 , VEGF , and PDGF . DNA G-quadruplexes, formed in the promoter region of these proto-oncogenes, are considered alternative anticancer targets since their stabilization causes a reduction of the related oncoprotein overexpression. In this study, a structure-based virtual screening toward the experimental DNA G-quadruplex structures of c-myc and c-Kit was performed by using Glide for the docking analysis of a commercial library of approximately 693 000 compounds. The best hits were submitted to thermodynamic and biophysical studies, highlighting the effective stabilization of both G-quadruplex oncogene promoter structures for three N -(4-piperidinylmethyl)amine derivatives, thus proposed as a new class of dual G-quadruplex binders., Competing Interests: The authors declare no competing financial interest.
- Published
- 2018
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39. Correction to Discovery of New Chemical Entities for Old Targets: Insights on the Lead Optimization of Chromone-Based Monoamine Oxidase B (MAO-B) Inhibitors.
- Author
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Reis J, Cagide F, Chavarria D, Silva T, Fernandes C, Gaspar A, Uriarte E, Remião F, Alcaro S, Ortuso F, and Borges F
- Published
- 2018
- Full Text
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40. Targeting Tumor Associated Carbonic Anhydrases IX and XII: Highly Isozyme Selective Coumarin and Psoralen Inhibitors.
- Author
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Melis C, Distinto S, Bianco G, Meleddu R, Cottiglia F, Fois B, Taverna D, Angius R, Alcaro S, Ortuso F, Gaspari M, Angeli A, Del Prete S, Capasso C, Supuran CT, and Maccioni E
- Abstract
A small library of psoralen carboxylic acids and their corresponding benzenesulfonamide derivatives were designed and synthesized to evaluate their activity and selectivity toward tumor associated human carbonic anhydrase (hCA) isoforms IX and XII. Both psoralen acids and sulfonamides exhibited potent inhibition of IX and XII isozymes in the nanomolar concentration range. However, psoralen acids resulted as the most selective in comparison with the corresponding benzenesulfonamide derivatives. Our data indicate that the psoralen scaffold is a promising starting point for the design of highly selective tumor associated hCA inhibitors., Competing Interests: The authors declare no competing financial interest.
- Published
- 2018
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41. The Mu.Ta.Lig. Chemotheca: A Community-Populated Molecular Database for Multi-Target Ligands Identification and Compound-Repurposing.
- Author
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Ortuso F, Bagetta D, Maruca A, Talarico C, Bolognesi ML, Haider N, Borges F, Bryant S, Langer T, Senderowitz H, and Alcaro S
- Abstract
For every lead compound developed in medicinal chemistry research, numerous other inactive or less active candidates are synthetized/isolated and tested. The majority of these compounds will not be selected for further development due to a sub-optimal pharmacological profile. However, some poorly active or even inactive compounds could live a second life if tested against other targets. Thus, new therapeutic opportunities could emerge and synergistic activities could be identified and exploited for existing compounds by sharing information between researchers who are working on different targets. The Mu.Ta.Lig (Multi-Target Ligand) Chemotheca database aims to offer such opportunities by facilitating information exchange among researchers worldwide. After a preliminary registration, users can (a) virtually upload structures and activity data for their compounds with corresponding, and eventually known activity data, and (b) search for other available compounds uploaded by the users community. Each piece of information about given compounds is owned by the user who initially uploaded it and multiple ownership is possible (this occurs if different users uploaded the same compounds or information pertaining to the same compounds). A web-based graphical user interface has been developed to assist compound uploading, compounds searching and data retrieval. Physico-chemical and ADME properties as well as substructure-based PAINS evaluations are computed on the fly for each uploaded compound. Samples of compounds that match a set of search criteria and additional data on these compounds could be requested directly from their owners with no mediation by the Mu.Ta.Lig Chemotheca team. Guest access provides a simplified search interface to retrieve only basic information such as compound IDs and related 2D or 3D chemical structures. Moreover, some compounds can be hidden to Guest users according to an owner's decision. In contrast, registered users have full access to all of the Chemotheca data including the permission to upload new compounds and/or update experimental/theoretical data (e.g., activities against new targets tested) related to already stored compounds. In order to facilitate scientific collaborations, all available data are connected to the corresponding owner's email address (available for registered users only). The Chemotheca web site is accessible at http://chemotheca.unicz.it.
- Published
- 2018
- Full Text
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42. Design, synthesis and biochemical evaluation of novel multi-target inhibitors as potential anti-Parkinson agents.
- Author
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Carradori S, Ortuso F, Petzer A, Bagetta D, De Monte C, Secci D, De Vita D, Guglielmi P, Zengin G, Aktumsek A, Alcaro S, and Petzer JP
- Subjects
- Acetylcholinesterase metabolism, Animals, Antioxidants chemical synthesis, Antioxidants chemistry, Butyrylcholinesterase metabolism, Cholinesterase Inhibitors chemical synthesis, Cholinesterase Inhibitors chemistry, Dose-Response Relationship, Drug, Electrophorus, Horses, Humans, Hydrazones chemical synthesis, Hydrazones chemistry, Models, Molecular, Molecular Structure, Monoamine Oxidase metabolism, Monoamine Oxidase Inhibitors chemical synthesis, Monoamine Oxidase Inhibitors chemistry, Structure-Activity Relationship, Antioxidants pharmacology, Cholinesterase Inhibitors pharmacology, Drug Design, Hydrazones pharmacology, Monoamine Oxidase Inhibitors pharmacology, Parkinson Disease drug therapy
- Abstract
New 4-(3-nitrophenyl)thiazol-2-ylhydrazone derivatives are proposed as dual-target-directed monoamine oxidase B (MAO-B) and acetylcholinesterase (AChE) inhibitors, as well as antioxidant agents, for the treatment of neurodegenerative disorders such as Parkinson's disease. Rational molecular design, target recognition and predicted pharmacokinetic properties have been evaluated by means of molecular modelling. Based on these properties, compounds were synthesized and evaluated in vitro as MAO-B and AChE inhibitors, and compared to the activities at their corresponding isozymes, monoamine oxidase A (MAO-A) and butyrylcholinesterase (BuChE), respectively. Anti-oxidant properties, potentially useful in the treatment of neurodegenerative disorders, have been also investigated in vitro. Among the evaluated compounds, three inhibitors may be considered as promising dual inhibitors of MAO-B and AChE, in vitro. MAO-B inhibition was also shown to be competitive and reversible for compound 19., (Copyright © 2017 Elsevier Masson SAS. All rights reserved.)
- Published
- 2018
- Full Text
- View/download PDF
43. Molecular recognition of a carboxy pyridostatin toward G-quadruplex structures: Why does it prefer RNA?
- Author
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Rocca R, Talarico C, Moraca F, Costa G, Romeo I, Ortuso F, Alcaro S, and Artese A
- Subjects
- Binding Sites, Molecular Docking Simulation, Molecular Dynamics Simulation, RNA chemistry, Aminoquinolines chemistry, Aminoquinolines pharmacology, G-Quadruplexes drug effects, Picolinic Acids chemistry, Picolinic Acids pharmacology, RNA metabolism
- Abstract
The pyridostatin (PDS) represents the lead compound of a family of G-quadruplex (G4) stabilizing synthetic small molecules based on a N,N'-bis(quinolinyl)pyridine-2,6-dicarboxamide scaffold. Its mechanism of action involves the induction of telomere dysfunction by competing for binding with telomere-associated proteins, such as human POT1. Recently, through a template-directed "in situ" click chemistry approach, a PDS derivative, the carboxypyridostatin (cPDS), was discovered. It has the peculiarity to exhibit high molecular specificity for RNA over DNA G4, while PDS is a good generic RNA and DNA G4-interacting small molecule. Structural data on the binding modes of these compounds are not available, and the selectivity mode of cPDS toward TERRA G4 is unknown too. Therefore, this work is aimed at rationalizing the selectivity of cPDS versus TERRA G4 by means of molecular dynamics and docking simulations, coupled to better understand the binding mode of these compounds to telomeric G4 structures. The comprehensive analysis of cPDS binding mode and its conformational behavior demonstrates the importance of the ligand conformation properties coupled with a remarkable solvation contribution. This work is expected to provide valuable clues for further rational design of novel and selective TERRA G4 binders., (© 2017 John Wiley & Sons A/S.)
- Published
- 2017
- Full Text
- View/download PDF
44. Chemoinformatic Database Building and in Silico Hit-Identification of Potential Multi-Targeting Bioactive Compounds Extracted from Mushroom Species.
- Author
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Maruca A, Moraca F, Rocca R, Molisani F, Alcaro F, Gidaro MC, Alcaro S, Costa G, and Ortuso F
- Abstract
Mushrooms are widely-consumed fungi which contain natural compounds that can be used both for their nutritive and medicinal properties, i.e., taking advantage of their antimicrobial, antiviral, antitumor, anti-allergic, immunomodulation, anti-inflammatory, anti-atherogenic, hypoglycemic, hepatoprotective and antioxidant effects. Currently, scientific interest in natural compounds extracted from the fungal species is increasing because these compounds are also known to have pharmacological/biological activity. Unfortunately, however, their mechanisms of action are often unknown, not well understood or have not been investigated in their entirety. Given the poly-pharmacological properties of bioactive fungal compounds, it was decided to carry out a multi-targeted approach to predict possible interactions occurring among bioactive natural fungal extracts and several macromolecular targets that are therapeutically interesting, i.e., proteins, enzymes and nucleic acids. A chemical database of compounds extracted from both edible and no-edible mushrooms was created. This database was virtually screened against 43 macromolecular targets downloaded from the Protein Data Bank website. The aim of this work is to provide a molecular description of the main interactions involving ligand/multi-target recognition in order to understand the polypharmacological profile of the most interesting fungal extracts and to suggest a design strategy of new multi-target agents., Competing Interests: The authors declare no conflict of interest.
- Published
- 2017
- Full Text
- View/download PDF
45. Coumarin versus Chromone Monoamine Oxidase B Inhibitors: Quo Vadis?
- Author
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Fonseca A, Reis J, Silva T, Matos MJ, Bagetta D, Ortuso F, Alcaro S, Uriarte E, and Borges F
- Subjects
- Alanine analogs & derivatives, Alanine pharmacology, Benzylamines pharmacology, Chromones chemical synthesis, Chromones chemistry, Clorgyline pharmacology, Coumarins chemical synthesis, Coumarins chemistry, Humans, Indans pharmacology, Kinetics, Ligands, Molecular Docking Simulation, Monoamine Oxidase chemistry, Monoamine Oxidase Inhibitors chemical synthesis, Monoamine Oxidase Inhibitors chemistry, Selegiline pharmacology, Structure-Activity Relationship, Chromones pharmacology, Coumarins pharmacology, Monoamine Oxidase metabolism, Monoamine Oxidase Inhibitors pharmacology
- Abstract
Because of the lack of significant disease-modifying drugs for neurodegenerative disorders, a pressing need for new chemical entities endowed with IMAO-B still exists. Within this framework, and for the first time, a study was performed to compare coumarin- and chomone-3-phenylcarboxamide scaffolds. Compounds 10a and 10b were the most potent, selective, and reversible noncompetitive IMAO-B. The benzopyrone sp
2 oxygen atom was found to be position independent and a productive contributor for the ligand-enzyme complex stability.- Published
- 2017
- Full Text
- View/download PDF
46. Identification of G-quadruplex DNA/RNA binders: Structure-based virtual screening and biophysical characterization.
- Author
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Rocca R, Moraca F, Costa G, Nadai M, Scalabrin M, Talarico C, Distinto S, Maccioni E, Ortuso F, Artese A, Alcaro S, and Richter SN
- Subjects
- Antineoplastic Agents chemistry, Antineoplastic Agents pharmacology, Binding Sites, Circular Dichroism, DNA chemistry, DNA drug effects, DNA genetics, Guanosine chemistry, High-Throughput Screening Assays, Ligands, Molecular Docking Simulation, Nucleic Acid Denaturation, Potassium chemistry, RNA chemistry, RNA drug effects, RNA genetics, RNA Stability, Spectrometry, Mass, Electrospray Ionization, Structure-Activity Relationship, Telomerase chemistry, Telomerase drug effects, Telomerase genetics, Temperature, Antineoplastic Agents metabolism, DNA metabolism, Drug Design, G-Quadruplexes drug effects, Guanosine metabolism, RNA metabolism, Telomerase metabolism
- Abstract
Background: Recent findings demonstrated that, in mammalian cells, telomere DNA (Tel) is transcribed into telomeric repeat-containing RNA (TERRA), which is involved in fundamental biological processes, thus representing a promising anticancer target. For this reason, the discovery of dual (as well as selective) Tel/TERRA G-quadruplex (G4) binders could represent an innovative strategy to enhance telomerase inhibition., Methods: Initially, docking simulations of known Tel and TERRA active ligands were performed on the 3D coordinates of bimolecular G4 Tel DNA (Tel
2 ) and TERRA (TERRA2 ). Structure-based pharmacophore models were generated on the best complexes and employed for the virtual screening of ~257,000 natural compounds. The 20 best candidates were submitted to biophysical assays, which included circular dichroism and mass spectrometry at different K+ concentrations., Results: Three hits were here identified and characterized by biophysical assays. Compound 7 acts as dual Tel2 /TERRA2 G4-ligand at physiological KCl concentration, while hits 15 and 17 show preferential thermal stabilization for Tel2 DNA. The different molecular recognition against the two targets was also discussed., Conclusions: Our successful results pave the way to further lead optimization to achieve both increased selectivity and stabilizing effect against TERRA and Tel DNA G4s., General Significance: The current study combines for the first time molecular modelling and biophysical assays applied to bimolecular DNA and RNA G4s, leading to the identification of innovative ligand chemical scaffolds with a promising anticancer profile. This article is part of a Special Issue entitled "G-quadruplex" Guest Editor: Dr. Concetta Giancola and Dr. Daniela Montesarchio., (Copyright © 2016 Elsevier B.V. All rights reserved.)- Published
- 2017
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47. Ligand binding to telomeric G-quadruplex DNA investigated by funnel-metadynamics simulations.
- Author
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Moraca F, Amato J, Ortuso F, Artese A, Pagano B, Novellino E, Alcaro S, Parrinello M, and Limongelli V
- Subjects
- Binding Sites, Molecular Conformation, Molecular Docking Simulation, Molecular Structure, Solvents, Spectrometry, Fluorescence, DNA chemistry, DNA metabolism, G-Quadruplexes, Ligands, Molecular Dynamics Simulation, Telomere chemistry, Telomere metabolism
- Abstract
G-quadruplexes (G4s) are higher-order DNA structures typically present at promoter regions of genes and telomeres. Here, the G4 formation decreases the replicative DNA at each cell cycle, finally leading to apoptosis. The ability to control this mitotic clock, particularly in cancer cells, is fascinating and passes through a rational understanding of the ligand/G4 interaction. We demonstrate that an accurate description of the ligand/G4 binding mechanism is possible using an innovative free-energy method called funnel-metadynamics (FM), which we have recently developed to investigate ligand/protein interaction. Using FM simulations, we have elucidated the binding mechanism of the anticancer alkaloid berberine to the human telomeric G4 ( d [AG
3 (T2 AG3 )3 ]), computing also the binding free-energy landscape. Two ligand binding modes have been identified as the lowest energy states. Furthermore, we have found prebinding sites, which are preparatory to reach the final binding mode. In our simulations, the ions and the water molecules have been explicitly represented and the energetic contribution of the solvent during ligand binding evaluated. Our theoretical results provide an accurate estimate of the absolute ligand/DNA binding free energy ([Formula: see text] = -10.3 ± 0.5 kcal/mol) that we validated through steady-state fluorescence binding assays. The good agreement between the theoretical and experimental value demonstrates that FM is a most powerful method to investigate ligand/DNA interaction and can be a useful tool for the rational design also of G4 ligands.- Published
- 2017
- Full Text
- View/download PDF
48. A Comparative Docking Strategy to Identify Polyphenolic Derivatives as Promising Antineoplastic Binders of G-quadruplex DNA c-myc and bcl-2 Sequences.
- Author
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Costa G, Rocca R, Moraca F, Talarico C, Romeo I, Ortuso F, Alcaro S, and Artese A
- Subjects
- Antineoplastic Agents chemistry, Humans, Molecular Docking Simulation methods, Molecular Dynamics Simulation, Polyphenols chemistry, Antineoplastic Agents pharmacology, DNA metabolism, G-Quadruplexes drug effects, Polyphenols pharmacology, Proto-Oncogene Proteins c-bcl-2 metabolism, Proto-Oncogene Proteins c-myc metabolism
- Abstract
Polyphenols are compounds ubiquitously expressed in plants and used for their multiple healthy effects in humans as anti-inflammatory, antimicrobial, antiviral, anticancer and immunomodulatory agents. Due to their ability to modulate the activity of multiple targets involved in carcinogenesis, polyphenols can be employed to inhibit the growth of cancer cells. Several studies reported their high affinity to different G-quadruplex DNA structures, including the oncogene promoters c-myc and bcl-2. In this work we applied a structure-based virtual screening approach in order to screen a database of polyphenolic derivatives and human metabolites against both c-myc and bcl-2 DNA G-quadruplex structures. A Delphinidine derivative was identified as the best "dual" candidate and, after molecular dynamics simulations, resulted able to well stabilize both receptors., (© 2016 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.)
- Published
- 2016
- Full Text
- View/download PDF
49. Hit Identification of a Novel Dual Binder for h-telo/c-myc G-Quadruplex by a Combination of Pharmacophore Structure-Based Virtual Screening and Docking Refinement.
- Author
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Rocca R, Costa G, Artese A, Parrotta L, Ortuso F, Maccioni E, Pinato O, Greco ML, Sissi C, Alcaro S, Distinto S, and Moraca F
- Subjects
- Humans, Drug Evaluation, Preclinical, G-Quadruplexes drug effects, Genes, myc drug effects, Molecular Docking Simulation, Promoter Regions, Genetic drug effects
- Abstract
It is well known that G-quadruplexes are targets of great interest for their roles in crucial biological processes, such as aging and cancer. Hence, a promising strategy for anticancer drug therapy is the stabilization of these structures by small molecules. We report a high-throughput in silico screening of commercial libraries from several different vendors by means of a combined structure-based pharmacophore model approach followed by docking simulations. The compounds selected by the virtual screening procedure were then tested for their ability to interact with human telomeric G-quadruplex folding by circular dichroism, fluorescence spectroscopy, and fluorescence intercalator displacement. Our approach resulted in the identification of a 13-[(dimethylamino)methyl]-12-hydroxy-8H-benzo[c]indolo[3,2,1-ij][1,5]naphthyridin-8-one derivative as a novel promising stabilizer of G-quadruplex structures within the human telomeric and the c-myc promoter sequences., (© 2016 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.)
- Published
- 2016
- Full Text
- View/download PDF
50. (E)-3-Heteroarylidenechroman-4-ones as potent and selective monoamine oxidase-B inhibitors.
- Author
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Desideri N, Proietti Monaco L, Fioravanti R, Biava M, Yáñez M, Alcaro S, and Ortuso F
- Subjects
- Chromans pharmacology, Humans, Hydrogen Bonding, Inhibitory Concentration 50, Models, Molecular, Monoamine Oxidase drug effects, Monoamine Oxidase Inhibitors pharmacology, Sensitivity and Specificity, Solvents pharmacology, Structure-Activity Relationship, Chromans chemistry, Monoamine Oxidase Inhibitors chemistry
- Abstract
A series of (E)-3-heteroarylidenechroman-4-ones (1a-r) was designed, synthesized and investigated in vitro for their ability to inhibit the enzymatic activity of both human monoamine oxidase (hMAO) isoforms, hMAO-A and hMAO-B. All the compounds were found to be selective hMAO-B inhibitors showing IC50 values in the nanomolar or micromolar range. (E)-5,7-Dichloro-3-{[(2-(dimethylamino)pyrimidin-5-yl]methylene}chroman-4-one (1c) was the most interesting compound identified in this study, endowed with higher hMAO-B potency (IC50 = 10.58 nM) and selectivity (SI > 9452) with respect to the reference selective inhibitor selegiline (IC50 = 19.60 nM, IC50 > 3431). Molecular modelling studies were performed for rationalizing at molecular level the target selective inhibition of our compounds, revealing a remarkable contribution of hydrogen bond network and water solvent., (Copyright © 2016 Elsevier Masson SAS. All rights reserved.)
- Published
- 2016
- Full Text
- View/download PDF
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