Computer aided molecular design of M. Turberculosis DNA gyrase inhibitors as novel and highly selective anti-tuberculosis agents

Molecular modeling and computer-aided molecular design approaches has become an essential tool in assisting fast and cost-efficient lead discovery and optimization. In the present study, molecular modeling and computer-aided molecular design approaches were applied to understand the molecular basis for developing new and more potent anti-tuberculosis agents. Mutations in DNA gyrase confer resistance to fluoroquinolones, second-line antibiotics for M. tuberculosis infections. The discovery of new anti-tuberculosis agents that inhibit M. tuberculosis DNA gyrase ATPase activity is one strategy to overcome this. Herein, bioisosteric designs using the known pyrrolamide inhibitor as a template were employed to define novel DNA gyrase inhibitors. Utilization of this modified compound as the template for virtual screening, supported by subsequent biological assays, identified M. tuberculosis DNA gyrase inhibitors with IC50 values better than that of the reference DNA gyrase inhibitor novobiocin. In addition, the new compounds showed non-cytotoxicity to Caco-2 cells at concentrations significantly higher than their IC50 values. MD simulations, followed by decomposition energy calculations identified that the promising compounds occupy the ATP binding site of M. tuberculosis GyrB. A compound containing the benzoindole fragment represents a potential new scaffold for further exploration and optimization as an M. tuberculosis DNA gyrase inhibitor and a candidate anti-tuberculosis agent. Discovery of novel DNA gyrase inhibitors, increasing attention has been paid to ATPase active against M. tuberculosis DNA gyrase of natural products. Knema belongs genus (K. globularia) is locally known as "lueat raet" in Thailand. The isolated compounds from the stems of K. globularia were tested for M. tuberculosis DNA gyrase ATPase activity and subsequent by anti-tuberculosis activity. These results were comparable to novobiocin. The new compounds showed active in both whole cell and enzyme inhibition assays. Then, MD simulations was performed to investigate the binding mode of the promising compounds in the ATP binding site of M. tuberculosis GyrB. The results demonstrated that the promising compounds interact strongly with the GyrB enzyme and that displayed good pharmacokinetic properties. Molecular docking calculations and MD simulations were applied to predict binding mode and binding interactions of benzo[d]isothiazole derivatives in the ATP binding site of M. smegmatis GyrB. The obtained results can be summarized to identify the structural requirements of benzo[d]isothiazole derivatives for the novel design of DNA gyrase ATPase inhibitors. Moreover, the dimeric structure of M. tuberculosis DNA gyrase ATPase in complex with the substrate ATP can catalyze negative supercoils into DNA. D-NEMD simulations were used to identify the structural effects of M. tuberculosis GyrB on ATP hydrolysis and how such changes are propagated through communication pathways connecting the ATP site to other functionally important regions of the GyrB ATPase domain. The simulations showed a striking pattern of communication between the ATP site and the GHKL and transducer regions, both of which are important to anti-tuberculosis drug resistance. The structural changes induced by ATP hydrolysis are transmitted through cooperative coupling of the ATP-lid of the GHKL domain and portions of the transducer domain. The amino side chain of Lys372 is in hydrogen bonding distance to the y-phosphate of the substrate analog and, thus, probably capable to stabilize the negative charge of the transition state. The use of D-NEMD simulations to study the ATPase domain of GyrB has significant implications for the development of new antituberculosis agents. These findings highlight the importance of understanding the mechanism behind the conformational changes in the ATPase domain of GyrB, which is crucial for enzyme function. By exploring valuable information, effective inhibitors can be designed as promising candidates for creating innovative classes of antituberculosis agents.