Title: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
Volume: 20
Issue: 8
Author(s): Mohammad Ramezani and Jamal Shamsara*
Affiliation:
- Pharmaceutical Research Center, Mashhad University of Medical Sciences, Mashhad,Iran
Keywords:
Computer aided drug design, docking, matrix metalloproteinase, MMP-13, osteoarthritis, virtual screening.
Abstract: Aim and Objective: 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.
Methods: 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.
Results: 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.
Conclusion: We discovered 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.
