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Virtual screening on MMP-13 led to discovering new inhibitors including a non-zinc binding and a micro molar one: a successful example of receptor selection according to cross-docking results for a flexible enzyme

Author(s):

Mohammad Ramezani and Jamal Shamsara  

Abstract:


MMP-13 belongs to a large family of proteases called matrix metalloproteinases (MMPs) that degrades type II collagen, the main structural protein of articular cartilage. The main pathologic role of MMP-13 over expression is to contribute to the development of osteoarthritis. To find new inhibitors with possible selectivity for MMP-13 a structure based virtual screening was employed. The inhibitory activities of 11 inhibitors among 19 purchased compounds were approved by enzyme inhibition assay. Our results demonstrated that the CADD (computer aided drug design) could be successfully applied to find new MMP-13 inhibitors using a receptor structure (PDB code: 3O2X) which had been demonstrated a good performance in a cross-docking study. We found inhibitors with new scaffolds for inhibition of MMP-13 and some selectivity features such as proper S1′ occupancy and interactions with S1′ pocket that could be subjected to a future lead optimization study.

Keywords:

Docking, Matrix metalloproteinases, MMP-13, Virtual screening

Affiliation:

Department of Biotechnology, School of Pharmacy, Mashhad University of Medical Sciences, Mashhad, Pharmaceutical Research Center, School of Pharmacy, Mashhad University of Medical Sciences, Mashhad



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