Molecular modeling of potential anti-tb agents active M.tuberculosis InhA and GyrB

In this research, computer aided molecular design (CAMD) approaches were applied to investigate the structural requirements of novel inhibitors as highly potnet anti-tuberculosis. The first enzyme target, enoyl-ACP reductase (InhA) of M.tuberculosis has been shown to be the primary target of the isoniazid. Because of the isoniazid resistance associated with catalase-peroxidase mutations, heteroaryl benzamide derivatives were developed as the novel direct InhA inhibitors. Molecular docking calculations, molecular dynamics (MD) simulations and three dimensional quantitative structure activity relationships (3D-QSAR) were applied to elucidate the important information and develop more potent InhA inhibitor. The second enzyme target is DNA gyrase subunit B (GyrB). The function of this enzyme is causes supercoiling of DNA which relieves strain during the DNA unwinding for M.tuberculosis. The fluoroquinolone resistance arises from the mutations of GyrB enzyme. Molecular docking calculations and MD simulations were applied to predict binding mode and binding interactions of 4-aminoquinoline dericatives. 3D-QSAR studied were used to investigate the structural requirements of 4-aminoquinoline derivatives to rational design new potent GyrB inhibitors. Therefore, the important information from this study were applied to understand the binding mode of inhibitors in binding pocket, the crucial interactions of inhibitors in binding pocket and the structure requirements of heteroaryl benzamide derivatives as InhA inhibitors and 4-aminoquinoline derivatives as GyrB inhibitors provided guidelines for the design of new and more potent InhA and GyrB inhibitors, and solve drug resistant problem of M.tuberculosis