Computational Design and In Silico Evaluation of Indole-2-Carboxamide Derivatives as Mycobacterium tuberculosis Membrane Protein (MmpL3) Inhibitors Using 2D-QSAR, Molecular Docking, and Molecular Dynamics Simulation

Background The development of inhibitors targeting membrane transport systems involved in mycobacterial cell wall biosynthesis remains an important pathway in antitubercular drug discovery. This study aimed to design and evaluate indole-2-carboxamide derivatives as potential inhibitors of mycobacterial membrane protein Large 3 (MmpL3) using an integrated computational approach. Methods A dataset of 46 indole-2-carboxamide derivatives was investigated using two-dimensional quantitative structure-activity relationship (2D-QSAR) modeling, molecular docking, pharmacokinetic prediction, molecular dynamics (MD) simulations, and MM-GBSA binding free energy analysis to evaluate activity determinants and binding stability. Results The developed QSAR model showed satisfactory predictive capability (R² = 0.646, Q²_LOO = 0.527, R²_ext = 0.636), highlighting key structural descriptors governing activity. Docking results identified compound 17 as a favorable scaffold with strong binding affinity (MolDock score: -146.758; pIC₅₀ = 6.7696). Structural optimization generated four analogues, among which compound 17c demonstrated the highest binding affinity (MolDock score: -159.019) and improved electrostatic, hydrogen-bonding, and hydrophobic interactions within the MmpL3 binding pocket. ADMET analysis predicted favourable drug-like properties and high intestinal absorption (> 90%). MD simulations revealed stable protein-ligand interactions with RMSD values of 2.4–4.8 Å, while MM-GBSA analysis showed strong binding free energy (ΔG_bind = -76.27 kcal/mol), surpassing compound 17 and reference drugs. Conclusion Compound 17c demonstrates promising inhibitory potential against MmpL3, with favorable binding stability and predicted pharmacokinetic properties. However, the study is limited by the absence of experimental validation; therefore, in vitro and in vivo studies are required to confirm the predicted biological activity and therapeutic potential of the proposed compounds.