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In Silico Study Combining Docking and QSAR Methods on a Series of Matrix Metalloproteinase 13 Inhibitors
Author(s) -
Xi Lili,
Li Shuyan,
Yao Xiaojun,
Wei Yuhui,
Li Jiazhong,
Liu Huanxiang,
Wu Xin'an
Publication year - 2014
Publication title -
archiv der pharmazie
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.468
H-Index - 61
eISSN - 1521-4184
pISSN - 0365-6233
DOI - 10.1002/ardp.201400200
Subject(s) - quantitative structure–activity relationship , docking (animal) , in silico , chemistry , stereochemistry , computational biology , molecular descriptor , dock , ligand (biochemistry) , biological system , combinatorial chemistry , receptor , biochemistry , biology , medicine , nursing , gene
Matrix metalloproteinase 13 (MMP‐13) plays an important role in the degradation of articular cartilage and has been considered as an attractive target for the treatment of osteoarthritis; hence, the development of efficient inhibitors of MMP‐13 has become a hot study field. Taking a series of carboxylic acid‐based MMP‐13 inhibitors as research object, this work utilized an extended QSAR method to analyze the structure–activity relationships. We focused on two important topics in QSAR: bioactive conformation and descriptors. Firstly, molecular docking was carried out to dock all molecules into the MMP‐13 active site in order to obtain the bioactive conformation. Secondly, based on the docked complex, descriptors characterizing receptor–ligand interactions and the ligand structure were calculated. Thirdly, a genetic algorithm (GA) and multiple linear regression (MLR) were employed to select important descriptors related to inhibitory activities, simultaneously, to build the predictive model. The built model gave satisfactory results with highly accurate fitting and strong external predictive abilities for chemicals not used in model development. Furthermore, the selected descriptors were explored to elucidate important factors influencing the inhibition activities. This study demonstrates that the selection strategy of the docking‐guided bioactive conformation is rational and useful in predicting MMP‐13 inhibitor activities, and receptor–ligand complex descriptors have an advantage over directly reflecting receptor–ligand interactions.