In-silico Insights into Some Novel Quinoline Derivatives: Docking, Simulation and ADME/Pharmacokinetic Prediction as Anti-tubercular Agents

Tuberculosis (TB) is one of the leading causes of death and needs concern at the global level. Dramatic changes have been seen in its treatment, from ongoing marketed drugs to drugs under clinical trials, and certain compounds have shown promising results for drug resistance and drug-susceptible issues. One such compound is quinoline and its scaffolds, which show excellent antitubercular activity (Bedaquiline) with less or no toxicity and are also successfully under clinical trials (TBAJ-876, Quabodepistat). In this study, we designed novel quinoline derivatives and predicted their pharmacokinetic profiles, demonstrating compliance with Lipinski's rule and showing favorable properties such as good gastrointestinal (GI) absorption, bioavailability, and drug-likeness properties. Further, molecular docking studies revealed that these derivatives showed a favorable interaction with the Deoxyribonucleic acid gyrase (DNA gyrase) (PDB:3IFZ) enzyme, with compounds 45, 48, and 53 showing the highest binding energies of - 8.33, - 7.8, and - 7.86 kcal/mol, respectively, than that of reference drug isoniazid. Additionally, molecular dynamic (MD) simulation was also performed for these three ligands (45, 48, and 53) to explore the dynamic of protein-ligand complexes within 100 ns trajectory. The values of root mean square deviation (RMSD) and root mean square fluctuation (RMSF) revealed that compound 45 remains comparatively more stable than other compounds. These findings support the potential of the designed compounds as promising lead candidates for treating multidrug-resistant TB, and their efficacy will be further evaluated in vitro and in vivo. This study highlights the novel approach of designing and evaluating quinoline derivatives for enhanced TB treatment, with promising prospects for drug development.