title: Computational Approaches to Matrix Metalloprotease Drug Design.
abstract: 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.
authors.affiliation: Department of Chemistry, Indian Institute of Technology, Hauz Khas, New Delhi, 110016, India.|Supercomputing Facility for Bioinformatics & Computational Biology, Indian Institute of Technology, Hauz Khas, New Delhi, 110016, India.
authors.forename: Tanya
authors.initials: T
authors.lastname: Singh
authors.affiliation: Department of Chemistry, Indian Institute of Technology, Hauz Khas, New Delhi, 110016, India. bjayaram@chemistry.iitd.ac.in.|Supercomputing Facility for Bioinformatics & Computational Biology, Indian Institute of Technology, Hauz Khas, New Delhi, 110016, India. bjayaram@chemistry.iitd.ac.in.|Kusuma School of Biological Sciences, Indian Institute of Technology, Hauz Khas, New Delhi, 110016, India. bjayaram@chemistry.iitd.ac.in.
authors.forename: B
authors.initials: B
authors.lastname: Jayaram
authors.affiliation: Department of Pharmacy, University of Tromsø, Tromsø, Norway.
authors.forename: Olayiwola Adedotun
authors.initials: OA
authors.lastname: Adekoya
mesh_terms: D020134:Catalytic Domain; D019295:Computational Biology / Q000379:methods*; D015195:Drug Design; D006801:Humans; D061965:Matrix Metalloproteinase Inhibitors / Q000737:chemistry / Q000494:pharmacology*; D020782:Matrix Metalloproteinases / Q000737:chemistry / Q000378:metabolism; D008958:Models, Molecular; D062105:Molecular Docking Simulation / Q000379:methods; D056004:Molecular Dynamics Simulation; D010649:Phenylalanine / Q000031:analogs & derivatives* / Q000737:chemistry / Q000494:pharmacology; D013876:Thiophenes / Q000737:chemistry / Q000494:pharmacology*
chemical_list: D061965:Matrix Metalloproteinase Inhibitors; D013876:Thiophenes; D010649:Phenylalanine; C080985:batimastat; D020782:Matrix Metalloproteinases
keywords: Computer-aided drug design; Docking and scoring; Matrix metalloprotease; Molecular dynamics simulations