Computational design, pharmacokinetics, molecular docking and molecular dynamic simulation of novel anti-tubercular inhibitors

Abstract

The rising threat of multidrug-resistant Mycobacterium tuberculosis (MDR-TB) has intensified the demand for novel therapeutic options. This study utilized a comprehensive computational approach to identify potential inhibitors targeting the DNA gyrase enzyme of M. tuberculosis . A selection of 40 anti-tubercular compounds underwent molecular docking to evaluate their binding affinity to the target protein. The top-performing molecules were assessed further using ADMET prediction tools to determine their pharmacokinetic properties and drug-likeness. To explore the electronic behaviour and stability of selected ligands, Density Functional Theory (DFT) calculations were conducted. Additionally, molecular dynamics (MD) simulations over 250 nanoseconds provided insights into the conformational stability of the protein-ligand complexes. The MM/GBSA method was employed to estimate binding free energies, supporting the molecular docking outcomes. Among the compounds, complexes 25 and 39 showed the highest binding affinities (-127.57 and -138.03 kcal/mol) respectively, outperforming standard anti-TB drugs; Isoniazid (-52.99 kcal/mol), Ethambutol (-68.92 kcal/mol), and Pyrazinamide (-60.16 kcal/mol). ADMET analysis confirmed acceptable oral bioavailability and low toxicity. DFT results revealed that compound 19 possessed favourable electronic characteristics. MD simulations demonstrated the structural stability of all complexes, with compound 19 showing minimal fluctuation throughout the trajectory. MM/GBSA results supported the docking findings, identifying compounds 25 and 39 as top binders with ΔG bind values of -48.32 and -49.30 kcal/mol, respectively. This study identifies compounds 25 and 39 as promising candidates for further investigation as multidrug-resistant anti-TB agents, given their high affinity for the target site, robust stability, and promising pharmacokinetic profiles.