3D-QSAR studies of arylcarboxamides with inhibitory activity on InhA using pharmacophore-based alignment.
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.
Lu
Xiao-Yun
XY
Department of Medicinal Chemistry, China Pharmaceutical University, Nanjing, China.
Chen
Ya-Dong
YD
You
Qi-Dong
QD
D000577:Amides / Q000737:chemistry* / Q000494:pharmacology; D000995:Antitubercular Agents / Q000737:chemistry* / Q000494:pharmacology; D003198:Computer Simulation; D050753:Enoyl-(Acyl-Carrier-Protein) Reductase (NADH) / Q000037:antagonists & inhibitors* / Q000378:metabolism; D007211:Indoles / Q000737:chemistry / Q000494:pharmacology; D016018:Least-Squares Analysis; D008956:Models, Chemical; D008958:Models, Molecular; D010879:Piperazines / Q000737:chemistry / Q000494:pharmacology; D021281:Quantitative Structure-Activity Relationship
D000577:Amides; D000995:Antitubercular Agents; C475580:GENZ10850; D007211:Indoles; D010879:Piperazines; D050753:Enoyl-(Acyl-Carrier-Protein) Reductase (NADH)