Computational Approaches to Matrix Metalloprotease Drug Design

Part of the Methods in Molecular Biology book series (MIMB, volume 1579)


Matrix metalloproteinases (MMPs) are a family of zinc-containing enzymes required for homeostasis. These enzymes are an important class of drug targets as their over expression is associated with many disease states. Most of the inhibitors reported against this class of proteins have failed in clinical trials due to lack of specificity. In order to assist in drug design endeavors for MMP targets, a computationally tractable pathway is presented, comprising, (1) docking of small molecule inhibitors against the target MMPs, (2) derivation of quantum mechanical charges on the zinc ion in the active site and the amino acids coordinating with zinc including the inhibitor molecule, (3) molecular dynamics simulations on the docked ligand–MMP complexes, and (4) evaluation of binding affinities of the ligand–MMP complexes via an accurate scoring function for zinc containing metalloprotein–ligand complexes. The above pathway was applied to study the interaction of the inhibitor Batimastat with MMPs, which resulted in a high correlation between the predicted and experimental binding free energies, suggesting the potential applicability of the pathway.

Key words

Matrix metalloprotease Computer-aided drug design Docking and scoring Molecular dynamics simulations 



This work is supported by grants from the Department of Biotechnology, Govt. of India. Tanya Singh is a recipient of Senior Research Fellowship from Council of Scientific & Industrial Research, Govt. of India.


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© Springer Science+Business Media LLC 2017

Authors and Affiliations

  1. 1.Department of ChemistryIndian Institute of TechnologyNew DelhiIndia
  2. 2.Supercomputing Facility for Bioinformatics & Computational BiologyIndian Institute of TechnologyNew DelhiIndia
  3. 3.Kusuma School of Biological SciencesIndian Institute of TechnologyNew DelhiIndia
  4. 4.Department of PharmacyUniversity of TromsøTromsøNorway

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