Exploring new scaffolds for angiotensin II receptor antagonism |
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| Institution: | 1. Institute of Biology, Medicinal Chemistry and Biotechnology, National Hellenic Research Foundation, 48, Vas. Constantinou Ave, Athens 11635, Greece;2. School of Chemical Engineering, Laboratory of Organic Chemistry, National Technical University of Athens (NTUA), 9, Iroon-Polytechneiou-Str, Athens 15773, Greece;3. Cloudpharm P.C., 190, Leoforos Syggrou, Athens 17671, Greece;4. Department of Pharmacology, School of Medicine, University of Crete, Heraklion, Crete 71003, Greece;5. Department of Pharmacy, Lab of Pharmacognosy and Chemistry of Natural Products, University of Patras, Patras 26504, Greece;6. Department of Chemistry, National and Kapodistrian University of Athens, Panepistimioupolis Zografou, Athens 15771, Greece;1. Faculty of Chemistry, Warsaw University of Technology, Noakowskiego 3, 00-664 Warsaw, Poland;2. Institute of Surface Chemistry, 17 General Naumov Street, 03164 Kiev, Ukraine;3. Faculty of Chemistry, Maria Curie-Sk?odowska University, 20-031 Lublin, Poland;1. Chuiko Institute of Surface Chemistry, 17 General Naumov Street, Kiev 03164, Ukraine;2. Frantsevich Institute for Problems of Materials Science, 3 Krzhyzhanovsky Street, Kyiv 03142, Ukraine;3. Maria Curie-Sklodowska University, Maria Curie-Sklodowska Sq. 3, Lublin 20-031, Poland;1. Institute of Biology, Pharmaceutical Chemistry and Biotechnology, National Hellenic Research Foundation, 48 Vas. Constantinou Ave., Athens 11635, Greece;2. Department of Chemistry, National and Kapodistrian University of Athens, Panepistimioupolis Zographou 15771, Greece;3. Department of Inorganic Chemistry, Faculty of Pharmacy, Wroc?aw Medical University, Szewska 38 PL-50139 Wroc?aw, Poland;4. National Center for Scientific Research “Demokritos”, Institute of Advanced Materials, Physicochemical Processes, Nanotechnology and Microsystems, Molecular Thermodynamics and Modelling of Materials Laboratory, GR-153 10, Aghia Paraskevi Attikis, Greece;5. Scienomics Sarl, 17 square Edouard VII, 75009 Paris, France |
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| Abstract: | Nowadays, AT1 receptor (AT1R) antagonists (ARBs) constitute the one of the most prevalent classes of antihypertensive drugs that modulate the renin-angiotensin system (RAS). Their main uses include also treatment of diabetic nephropathy (kidney damage due to diabetes) and congestive heart failure. Towards this direction, our study has been focused on the discovery of novel agents bearing different scaffolds which may evolve as a new class of AT1 receptor antagonists. To fulfill this aim, a combination of computational approaches and biological assays were implemented. Particularly, a pharmacophore model was established and served as a 3D search query to screen the ChEMBL15 database. The reliability and accuracy of virtual screening results were improved by using molecular docking studies. In total, 4 compounds with completely diverse chemical scaffolds from potential ARBs, were picked and tested for their binding affinity to AT1 receptor. Results revealed high nanomolar to micromolar affinity (IC50) for all the compounds. Especially, compound 4 exhibited a binding affinity of 199 nM. Molecular dynamics simulations were utilized in an effort to provide a molecular basis of their binding to AT1R in accordance to their biological activities. |
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| Keywords: | Angiotensin II receptor antagonists Pharmacophore modeling Virtual screening Pharmacological characterization Molecular Dynamics simulations |
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