Computational design of MmpL3 inhibitors for tuberculosis therapy

Tuberculosis is a chronic communicable disease caused by Mycobacterium tuberculosis (Mtb) and spreads from lungs to lymphatic system. The cell wall of mycobacterium plays a prominent role in maintaining the virulence and pathogenicity and also acts as prime target for drug discovery. Hence, this study has put into emphasis with target MmpLs (Mycobacterial membrane proteins Large) which are significant for the growth and survival of Mycobacterium tuberculosis. MmpLs belongs to the resistance, nodulation and division (RND) protein superfamily. MmpL3 is the only MmpL deemed essential for the replication and viability of mycobacterial cells. For the study, we have selected SQ109 derivatives as Mmpl3 inhibitor, which holds non-covalent property. Structure-based pharmacophore model of MmpL3 target protein with SQ109 as co-crystallized ligand (PDB: 6AJG) was generated to screen the ligand database. Compounds with decent fitness score and pharmacophoric features were compared with standard drug and taken for molecular docking studies. Further prime molecular mechanics-Poisson-Boltzmann surface area (MM-GBSA) and induced fit calculations identified potential molecules for further drug-likeness screening. Overall computational calculations identified ZINC000000016638 and ZINC000000003594 as potential in silico MmpL3 inhibitors. Molecular dynamics simulations integrated with MM-PBSA free energy calculations identified that MmpL3-ZINC000000016638 complex was more stable. Study can be further extended for synthesis and biological evaluation, derivatization of active compound to identify potential and safe lead compounds for effective tuberculosis therapy.