Τίτλος:
Exploring new scaffolds for angiotensin II receptor antagonism
Γλώσσες Τεκμηρίου:
Αγγλικά
Περίληψη:
Nowadays, AT1receptor (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 AT1receptor 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 AT1receptor. 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. © 2016 Elsevier Ltd
Συγγραφείς:
Kritsi, E.
Matsoukas, M.-T.
Potamitis, C.
Karageorgos, V.
Detsi, A.
Magafa, V.
Liapakis, G.
Mavromoustakos, T.
Zoumpoulakis, P.
Περιοδικό:
BIOORGANIC AND MEDICINAL CHEMISTRY
Εκδότης:
Elsevier Ireland Ltd
Λέξεις-κλειδιά:
angiotensin 1 receptor; angiotensin receptor antagonist; olmesartan; angiotensin receptor antagonist; ligand, Article; binding affinity; controlled study; crystal structure; drug design; drug screening; drug structure; IC50; in vitro study; molecular docking; molecular dynamics; pharmacophore; physical chemistry; structure activity relation; three dimensional imaging; validation process; chemistry; drug effects; receiver operating characteristic; validation study, Angiotensin Receptor Antagonists; Inhibitory Concentration 50; Ligands; Molecular Dynamics Simulation; Receptor, Angiotensin, Type 1; ROC Curve
DOI:
10.1016/j.bmc.2016.07.047
