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Insight into the structural requirements of benzimidazole derivatives as interleukin‐2 inducible t‐cell kinase inhibitors by computational explorations
Author(s) -
Wang Jinghui,
Li Feng,
Li Yan,
Yang Yinfeng,
Wang Bin,
Zhang Shuwei,
Yang Ling
Publication year - 2013
Publication title -
international journal of quantum chemistry
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.484
H-Index - 105
eISSN - 1097-461X
pISSN - 0020-7608
DOI - 10.1002/qua.24470
Subject(s) - benzimidazole , in silico , chemistry , quantitative structure–activity relationship , stereochemistry , docking (animal) , molecular dynamics , ligand (biochemistry) , molecular model , hydrogen bond , structural similarity , combinatorial chemistry , computational biology , receptor , computational chemistry , molecule , biochemistry , biology , gene , medicine , nursing , organic chemistry
In the present work, a set of ligand‐ and receptor‐based 3D‐QSAR models were developed to explore the structure–activity relationship of 109 benzimidazole‐based interleukin‐2‐inducible T‐cell kinase (ITK) inhibitors. In order to reveal the requisite 3D structural features impacting the biological activities, a variety of in silico modeling approaches including the comparative molecular field analysis (CoMFA), comparative molecular similarity indices analysis (CoMSIA), docking, and molecular dynamics were applied. The results showed that the ligand‐based CoMFA model ( Q 2 = 0.552, R 2 ncv = 0.908, R 2 pred = 0.787, SEE = 0.252, SEP = 0.558) and CoMSIA model ( Q 2 = 0.579, R 2 ncv = 0.914, R 2 pred = 0.893, SEE = 0.240, SEP = 0.538) were superior to other models with greater predictive power. In addition, a combined analysis between the 3D contour maps and docking results showed that: (1) Compounds with bulky or hydrophobic substituents near ring D and electropositive or hydrogen acceptor groups around rings C and D could increase the activity. (2) The key amino acids impacting the receptor–ligand interactions in the binding pocket are Met438, Asp500, Lys391, and Glu439. The results obtained from this work may provide helpful guidelines in design of novel benzimidazole analogs as inhibitors of ITK. © 2013 Wiley Periodicals, Inc.