Abstract
Tuberculosis (TB), an infectious disease remains a major public health concern in Thailand. This research, we focused on design and discovery of potent anti-tuberculosis agents to overcome fluoroquinolone drug resistant using molecular modeling, computer aided molecular design approaches combined with biological assay evaluations. In order to design and develop structure of DNA gyrase inhibitors targeting at ATPase domain of DNA gyrase subunit B including 4-aminoquinoline, 4-(piperazin-1-yl)quinolone, 2-(1H-benzo[d]imidazol-2-yl)-2-cyanovinyl, Nitro-thaizole and benzo[d]isothiazole derivatives, molecular docking calculations, quantitative structure–activity relationship (QSAR), molecular dynamics (MD) simulations and FMO calculations were performed. The crucial interactions in ATPase domain and structural requirement of inhibitors revealed the key information for ration design highly potent DNA gyrase inhibitors. Virtual screening and biological assay were applied to discovery of novel and highly potent DNA gyrase inhibitors. 17 compounds showed the inhibitory activity based on ATPase assay closed to reference compound, Novobiocin. For antimicrobial assay, two active compounds, G24 and G26 were obtained the 12.5 µg/ml. DNA supercoiling assay of active compounds in wild-type and N538D mutant type of DNA gyrase were investigated. The obtained results showed that the inhibitory activity of two compounds (G18 and G24) were higher potent than the reference drug, ciprofloxacin. There active compounds (G18, G22 and G24) showed the DNA supercoiling inhibition higher than the reference drug. Pharmacokinetic properties of active compounds were predicted using ADMET predictions. The obtained results revealed that new active compounds were suitable for structural modification to improve the biological activity. MD simulations and X-ray crystallography were used to investigate the binding mode and binding interactions of active compounds in ATPase domain. The obtained results provided the crucial interactions for developing novel and highly potent compounds for fluoroquinolone drug resistant tuberculosis.
