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A combined molecular modeling study on gelatinases and their potent inhibitors
Author(s) -
Xi Lili,
Du Juan,
Li Shuyan,
Li Jiazhong,
Liu Huanxiang,
Yao Xiaojun
Publication year - 2009
Publication title -
journal of computational chemistry
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.907
H-Index - 188
eISSN - 1096-987X
pISSN - 0192-8651
DOI - 10.1002/jcc.21279
Subject(s) - quantitative structure–activity relationship , gelatinases , chemistry , computational biology , molecular model , docking (animal) , matrix metalloproteinase inhibitor , matrix metalloproteinase , stereochemistry , biochemistry , gelatinase , biology , medicine , nursing
Zinc‐dependent matrix metalloproteinase (MMP) family is considered to be an attractive target because of its important role in many physiological and pathological processes. In the present work, a molecular modeling study combining protein‐, ligand‐ and complex‐based computational methods was performed to analyze a new series of β‐ N ‐biaryl ether sulfonamide hydroxamates as potent inhibitors of gelatinase A (MMP‐2) and gelatinase B (MMP‐9). Firstly, the similarities and differences between the binding sites of MMP‐2 and MMP‐9 were analyzed through sequence alignment and structural superimposition. Secondly, in order to extract structural features influencing the activities of these inhibitors, quantitative structure‐activity relationship (QSAR) models using genetic algorithm‐multiple linear regression (GA‐MLR), comparative molecular field (CoMFA) and comparative molecular similarity indices analysis (CoMSIA) were developed. The proposed QSAR models could give good predictive ability for the studied inhibitors. Thirdly, docking study was employed to further explore the binding mode between the ligand and protein. The results from all the above analyses could provide the information about the similarities and differences of the binding mode between the MMP‐2, MMP‐9 and their potent inhibitors. The obtained results can provide very useful information for the design of new potential inhibitors. © 2009 Wiley Periodicals, Inc. J Comput Chem 2010