Molecular modeling of angiotensin type 1 receptor for angiotensin receptor blockers

Diabetic nephropathy is characterized by progressive persistent proteinuria, hypertension, decline in renal function by decreasing glomerular filtration rate, and risk of cardiovascular disease. Recently, agents (ARBs) developed with antihypertensive and antiproteinuric efficacy that block the RAS by preventing angiotensin II from binding to its subtype1 (AT1) receptor, belong to the family of GPCRs. Hence efforts are to design the drug molecules to inhibition of angiotensin receptor blockers by using bioinformatics tools. SBDD confirms the angiotensin II binds to the AT1 receptor within the transmembrane domains in an extended conformation, and its C-terminal residue interacts with transmembrane domain VII at Phe-293/Asn-294.Methionine proximity assay, determine the molecular environment of this binding pocket (L112M and Y113M in TMD III; F249M, W253M, H256M, and T260M in TMD VI; and F293M, N294M, N295M, C296M, and L297M in TMD VII.). Based on information of Target protein id P30556 in Uniprot, Pubmed all and I-TASSER that allow to automatically generate high-quality predictions of 3D structure and biological function of protein molecules based on C-Score and TM-Score. SPICKER clustered simulated decoys and top five cluster centroids are selected for generating full atomic models. Target protein's ligand binding site was predicted by using both Q-Site Finder and Pocket Finder. Drug bank, clinical trials database was used for finding the drug molecule to blocking the angiotesin receptor type1 and drawing a ligand molecule in ACD/CHEMSKETCHI based on the ligand binding site and 2D-CORINA used in 2D to 3D convertions. Blind docking method dock the protein and small molecule at correct functional site. Based on Dock database calculation save the molecule in pdb format and view in PyMol and tools are used to finding the drug likeliness satisfying 5 Lipinski’s rules.