Virtual screening and molecular dynamics simulation study of hECE-1 protease inhibitors

Human Endothelin Converting Enzyme-1 (ECE-1) is a type II integral membrane protein expressed by endothelial cells of the aorta, lungs, ovary and testis. The role of hECE-1 is to convert big endothelin (ET) into small ET-1. This functional ET-1 acts as a vasoconstrictor. It has been implicated in pathophysiology of cardiac diseases including hypertension, vascular hypertrophy and arthrosclerosis. Regulation of endothelin could be useful in number of cardiovascular diseases. In this study we screened ZINC database using Dockblatster to find out novel inhibitors of hECE-1. Screened compounds were filtered on the basis Lipinski’s rule. The selected compounds were then docked using PyRx tool. Finally, ligands ZINC31078067 and ZINC31075404 having lower energy re-docked using Autodock 4.2 by considering Asn 466, Glu 567 and His 632 as flexible residues of hECE1. A fully solvated molecular dynamics (MD) simulation was performed on docked complexes. The hECE-1inhibitor complex was found stable throughout the simulation period. The conserved residues 565 VNA 567 of hECE-1 and Zn 2+ forms strong hydrogen bonding interaction with inhibitor. The selected ligand ZINC-31078067 and ZINC31075404 would act as new potent and selective inhibitors of hECE-1 which could be used as lead drug candidates in the cardiovascular diseases.