title: Exploring new scaffolds for angiotensin II receptor antagonism.
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 199nM. Molecular dynamics simulations were utilized in an effort to provide a molecular basis of their binding to AT1R in accordance to their biological activities.
authors.affiliation: Institute of Biology, Medicinal Chemistry and Biotechnology, National Hellenic Research Foundation, 48, Vas. Constantinou Ave, Athens 11635, Greece; School of Chemical Engineering, Laboratory of Organic Chemistry, National Technical University of Athens (NTUA), 9, Iroon-Polytechneiou-Str, Athens 15773, Greece.
authors.forename: Eftichia
authors.initials: E
authors.lastname: Kritsi
authors.affiliation: Cloudpharm P.C., 190, Leoforos Syggrou, Athens 17671, Greece.
authors.forename: Minos-Timotheos
authors.initials: MT
authors.lastname: Matsoukas
authors.affiliation: Institute of Biology, Medicinal Chemistry and Biotechnology, National Hellenic Research Foundation, 48, Vas. Constantinou Ave, Athens 11635, Greece.
authors.forename: Constantinos
authors.initials: C
authors.lastname: Potamitis
authors.affiliation: Department of Pharmacology, School of Medicine, University of Crete, Heraklion, Crete 71003, Greece.
authors.forename: Vlasios
authors.initials: V
authors.lastname: Karageorgos
authors.affiliation: School of Chemical Engineering, Laboratory of Organic Chemistry, National Technical University of Athens (NTUA), 9, Iroon-Polytechneiou-Str, Athens 15773, Greece.
authors.forename: Anastasia
authors.initials: A
authors.lastname: Detsi
authors.affiliation: Department of Pharmacy, Lab of Pharmacognosy and Chemistry of Natural Products, University of Patras, Patras 26504, Greece.
authors.forename: Vasilliki
authors.initials: V
authors.lastname: Magafa
authors.affiliation: Department of Pharmacology, School of Medicine, University of Crete, Heraklion, Crete 71003, Greece.
authors.forename: George
authors.initials: G
authors.lastname: Liapakis
authors.affiliation: Department of Chemistry, National and Kapodistrian University of Athens, Panepistimioupolis Zografou, Athens 15771, Greece.
authors.forename: Thomas
authors.initials: T
authors.lastname: Mavromoustakos
authors.affiliation: Institute of Biology, Medicinal Chemistry and Biotechnology, National Hellenic Research Foundation, 48, Vas. Constantinou Ave, Athens 11635, Greece. Electronic address: pzoump@eie.gr.
authors.forename: Panagiotis
authors.initials: P
authors.lastname: Zoumpoulakis
mesh_terms: D057911:Angiotensin Receptor Antagonists / Q000737:chemistry / Q000494:pharmacology*; D020128:Inhibitory Concentration 50; D008024:Ligands; D056004:Molecular Dynamics Simulation; D012372:ROC Curve; D044140:Receptor, Angiotensin, Type 1 / Q000187:drug effects*
chemical_list: D057911:Angiotensin Receptor Antagonists; D008024:Ligands; D044140:Receptor, Angiotensin, Type 1
keywords: Angiotensin II receptor antagonists; Molecular Dynamics simulations; Pharmacological characterization; Pharmacophore modeling; Virtual screening