A QSAR study on the inhibition mechanism of matrix metalloproteinase-12 by arylsulfone analogs based on molecular orbital calculations

Seiji Hitaoka, Hiroshi Chuman, Kazunari Yoshizawa

Research output: Contribution to journalArticle

11 Citations (Scopus)

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.

Original languageEnglish
Pages (from-to)793-806
Number of pages14
JournalOrganic and Biomolecular Chemistry
Volume13
Issue number3
DOIs
Publication statusPublished - Jan 21 2015

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Matrix Metalloproteinase 12
Hydroxamic Acids
Orbital calculations
Quantitative Structure-Activity Relationship
Molecular orbitals
Carboxylic Acids
Free energy
Zinc
molecular orbitals
analogs
Pulmonary diseases
matrices
fragments
Matrix Metalloproteinase Inhibitors
carboxylic acids
Chronic Obstructive Pulmonary Disease
energy
zinc
free energy
interactions

All Science Journal Classification (ASJC) codes

  • Biochemistry
  • Physical and Theoretical Chemistry
  • Organic Chemistry

Cite this

A QSAR study on the inhibition mechanism of matrix metalloproteinase-12 by arylsulfone analogs based on molecular orbital calculations. / Hitaoka, Seiji; Chuman, Hiroshi; Yoshizawa, Kazunari.

In: Organic and Biomolecular Chemistry, Vol. 13, No. 3, 21.01.2015, p. 793-806.

Research output: Contribution to journalArticle

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