Identification of potential human chymase inhibitors using molecular docking and molecular dynamics simulation

Abstract

Chymase is a hydrolase class of enzymes that involves  hydrolysis of peptide bonds. It is abundant in secretory granules of mast cells. Mast cell chymase is involved in the synthesis of angiotensin-II from its precursor protein. In addition, chymase is involved in converting TGF-β and matrix metalloproteinase to their active form. Chymase involved in heart failure has been proven, and its inhibition may reduce the progression. Hence, to identify the potential inhibitors against the chymase, the present study employed structure-based virtual screening, molecular docking, and molecular dynamics simulation to identify potential chymase inhibitors. Initially, compounds were selected based on their physicochemical and pharmacokinetic properties. Further, the binding affinities using molecular docking and interaction analyses were performed to find potential chymase inhibitors. The study identified chymase inhibitor ZINC000008382327, bearing significant binding affinity, specificity, and efficacy towards the chymase. Next, the stability and binding mode of chymase with ZINC000008382327 were assessed using molecular dynamics simulations. The simulation analysis using root mean square deviations and fluctuations revealed that inhibitor ZINC000008382327 affected the structure and dynamics of the chymase protein. It was also shown that the chymase forms a stable complex with ZINC000008382327 during the simulation. Thus, the present computational study put forward that the identified compound can be further exploited as a potential chemical scaffold to design and develop new human chymase inhibitors.