In silico trials to design potent inhibitors against matrilysin (MMP-7)
Abstract
The study deals with structure-based rational drug design against the chief zinc-rely endopeptidase called matrilysin (MMP-7) that is involved in inflammatory and metastasis process of several carcinomas. Hyperactivated matrilysin of human was targeted, because of its hydrolytic actions on extracellular matrix (ECM) protein components constitutes fibrillar collagens, gelatins, fibronectins and it also activates zymogen forms of vital matrix metalloproteinases (gelatinase A-MMP-2 and B-MMP-9) responsible for ECM destruction in many cancers. In the present work, e-pharmacophores were generated for the respective five co-crystal structures of human matrilysin by mapping ligand's pharmacophoric features. During the lead-optimization campaign, the five e-pharmacophores-based shape screening against an in-house library of >21 million compounds created a dataset of 5000 structural analogs. The subsequent three different docking strategies, including rigid-receptor docking, quantum-polarized-ligand docking, induced-fit docking and free energy binding calculations resulted four leads as novel and potent MMP-7 binders. These four leads were observed with good pharmacological features and good receiver operating characteristics curve metrics (ROC: 0.93) in post-docking evaluations against five existing co-crystal inhibitors and 1000 decoy molecules with MMP-7. Moreover, stability and dynamics behavior of matrilysin-lead1 complex and matrilysin-cocrystal ligand (TQJ) complex were…
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