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3D‐QSAR studies of arylcarboxamides with inhibitory activity on InhA using pharmacophore‐based alignment
Author(s) -
Lu XiaoYun,
Chen YaDong,
You QiDong
Publication year - 2010
Publication title -
chemical biology and drug design
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.59
H-Index - 77
eISSN - 1747-0285
pISSN - 1747-0277
DOI - 10.1111/j.1747-0285.2009.00926.x
Subject(s) - pharmacophore , inha , protein data bank (rcsb pdb) , quantitative structure–activity relationship , chemistry , virtual screening , stereochemistry , computational biology , biology , medicine , tuberculosis , pathology , isoniazid
Enoyl acyl carrier protein reductase (InhA) is a promising target for the development of antituberculosis drugs. The InhA‐bound conformation of an indole‐5‐amide inhibitor (Genz 10850) (PDB code: IP44) was used to build a pharmacophore model by LigandScout. This model was then successfully used to identify the bioactive conformation and align 40 structurally diverse arylcarboxamide derivatives. Comparative molecular field analysis (CoMFA) and comparative molecular similarity indices analysis (CoMSIA) were performed on arylcarboxamides‐based InhA inhibitors based on pharmacophore alignment. The best prediction was obtained with CoMSIA model combining steric and electrostatic fields (, r 2 = 0.972). The model was validated by an external test set, which gave a good predictive value (). Graphical interpretation of the results revealed important structural features of the zarylcarboxamides related to the active site of InhA. The results may be exploited for further design and virtual screening for some novel InhA inhibitors.