title: A QSAR study on the inhibition mechanism of matrix metalloproteinase-12 by arylsulfone analogs based on molecular orbital calculations.
abstract: A binding mechanism between human matrix metalloproteinase-12 (MMP-12) and eight arylsulfone analogs having two types of carboxylic and hydroxamic acids as the most representative zinc binding group is investigated using a quantitative structure-activity relationship (QSAR) analysis based on a linear expression by representative energy terms (LERE). The LERE-QSAR analysis quantitatively reveals that the variation in the observed (experimental) inhibitory potency among the arylsulfone analogs is decisively governed by those in the intrinsic binding and dispersion interaction energies. The results show that the LERE-QSAR analysis not only can excellently reproduce the observed overall free-energy change but also can determine the contributions of representative free-energy changes. An inter-fragment interaction energy difference (IFIED) analysis based on the fragment molecular orbital (FMO) method (FMO-IFIED) leads to the identification of key residues governing the variation in the inhibitory potency as well as to the understanding of the difference between the interactions of the carboxylic and hydroxamic acid zinc binding groups. The current results that have led to the optimization of the inhibitory potency of arylsulfone analogs toward MMP-12 to be used in the treatment of chronic obstructive pulmonary disease may be useful for the development of a new potent MMP-12 inhibitor.
authors.affiliation: Institute for Materials Chemistry and Engineering and International Research Center for Molecular System, Kyushu University, Fukuoka 819-0395, Japan. kazunari@ms.ifoc.kyushu-u.ac.jp.
authors.forename: Seiji
authors.initials: S
authors.lastname: Hitaoka
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Chuman
authors.forename: Kazunari
authors.initials: K
authors.lastname: Yoshizawa
mesh_terms: D001665:Binding Sites; D002264:Carboxylic Acids / Q000138:chemical synthesis / Q000737:chemistry*; D006801:Humans; D006877:Hydroxamic Acids / Q000138:chemical synthesis / Q000737:chemistry*; D053508:Matrix Metalloproteinase 12 / Q000737:chemistry*; D061965:Matrix Metalloproteinase Inhibitors / Q000138:chemical synthesis / Q000737:chemistry*; D062105:Molecular Docking Simulation; D011485:Protein Binding; D021281:Quantitative Structure-Activity Relationship; D011789:Quantum Theory; D012996:Solutions; D013450:Sulfones / Q000138:chemical synthesis / Q000737:chemistry*; D013816:Thermodynamics; D015032:Zinc / Q000737:chemistry*
chemical_list: D002264:Carboxylic Acids; D006877:Hydroxamic Acids; D061965:Matrix Metalloproteinase Inhibitors; D012996:Solutions; D013450:Sulfones; C507122:MMP12 protein, human; D053508:Matrix Metalloproteinase 12; D015032:Zinc