title: Receptor-based 3D-QSAR approach to find selectivity features of flexible similar binding sites: case study on MMP-12/MMP-13.
abstract: Design of selective matrix metalloproteinases (MMPs) inhibitors is still a challenging task because of binding pocket similarities and flexibility among MMPs family. To overcome this issue we try to generate a (three-dimensional quantitative structure activity relationship) 3D-QSAR model that might reflect, at least in part, the differential properties of MMP-12 and MMP-13 active sites compared to each other. The different alignment rules were applied for CoMFA/CoMSIA model development. In an approach the best docked poses were followed by alignment based on their zinc binding group. As it was suggested by comparison of CoMSIA contour maps of MMP-12 with MMP-13, the ligand based approach can find more detailed features of specificity for MMPs that have similar highly flexible active sites, than solely analysis of available crystal structures. The residues Val(194), Leu(214) and Thr(220) of MMP-13 were suggested to be investigated for flexibility upon binding of different ligands.
authors.affiliation: 1 Department of Medicinal Chemistry, School of Pharmacy, Mashhad University of Medical Sciences, Mashhad, Iran; Biotechnology Research Center, School of Pharmacy, Mashhad University of Medical Sciences, Mashhad, Iran.
authors.forename: Farzin
authors.initials: F
authors.lastname: Hadizadeh
authors.affiliation: 2 Pharmaceutical Research Center, School of Pharmacy, Mashhad University of Medical Sciences, Mashhad, Iran.
authors.forename: Jamal
authors.initials: J
authors.lastname: Shamsara
mesh_terms: D001665:Binding Sites; D019295:Computational Biology / Q000379:methods*; D053508:Matrix Metalloproteinase 12 / Q000737:chemistry / Q000378:metabolism; D053509:Matrix Metalloproteinase 13 / Q000737:chemistry / Q000378:metabolism; D061965:Matrix Metalloproteinase Inhibitors / Q000737:chemistry / Q000378:metabolism; D008958:Models, Molecular; D011487:Protein Conformation; D021281:Quantitative Structure-Activity Relationship
chemical_list: D061965:Matrix Metalloproteinase Inhibitors; D053509:Matrix Metalloproteinase 13; D053508:Matrix Metalloproteinase 12
keywords: 3D-QSAR; CoMFA; CoMSIA; MMP-12; MMP-13; binding pocket similarities; binding sites; bioinformatics; case study; flexibility; inhibitors; ligands; metalloproteinases; modelling; quantitative structure activity relationship; receptors; selective matrix MMPs; selectivity features; zinc binding group