Discovery of potential new InhA direct inhibitors based on pharmacophore and 3D-QSAR analysis followed by in silico screening.

摘要

This study develops an efficient approach for discovering new InhA direct inhibitors in theory. The InhA-bound conformation of a pyrrolidine carboxamide inhibitor was used to build a pharmacophore model. This model with feature-shape query was successfully used to identify and align the bioactive conformations of pyrrolidine carboxamide analogues and screen SPECS database. A statistically valid 3D-QSAR with good results (r(2)(cv)=0.660 and r(2)=0.962) was obtained. From database screening, 30 hits were selected and identified as potential leads, which exhibit good estimated activities by 3D-QSAR model. Docking studies were carried out on two representative hits to analyze their interactions with InhA. Also, the interactions between existing pyrazole inhibitors and InhA were explored based on the pharmacophore model.