Rational Design of M. Tuberculosis DNA GYRASE Inhibitors in a Series of 4-Aminoquinoline Derivatives: Molecular Docking Calculation and 3d-Qsar COMSIA
Mutations of fluoroquinolone drug binding site of DNA gyrase are the majority problems of fluoroquinolone drug resistant. Therefore, new inhibitors that they can inhibit ATPase domain of DNA gyrase have been interested to overcome this drug resistant problem. 4-aminoquinoline derivatives were developed as new ATPase inhibitors for anti-tuberculosis agents. This work, we aim to rational design of new highly potent DNA gyrase inhibitors based on molecular docking calculation and 3D-QSAR CoMSIA model. Molecular docking calculation revealed that hydrogen bond interactions of ligand with Asn64, Asn37, Arg67, Thr154, Glul41, Tyr99, Thr94 and Thr98 residue and cation-π interactions were crucial for binding in the active site of inhibitors. The 3D-QSAR CoMSIA model included four descriptors (steric, hydrogen bond acceptor, electrostatic and hydrophobic) showed satisfactory statistical results (q2 = 0.682, r2 = 0.939, F value = 139.153). The structural requirements of M. tuberculosis DNA Gyrase inhibitors were derived from best CoMSIA of contour maps. The combine results aid to rational design new and more potent ATPase inhibitors as novel anti-tuberculosis.
Keywords - 4-Aminoquinoline, Molecular Docking, QSAR COMSIA, Anti-tuberculosis, DNA GYRASE Inhibitors.