Unraveling the possible inhibitors for Chorismate synthase to combat tuberculosis using in silico approach

Tuberculosis antibiotic resistance is a huge concern to the global population. The goal of this study was to find new and effective compounds to treat multidrug-resistant tuberculosis by targeting Chorismate synthase (CS), a crucial enzyme for Mycobacterium tuberculosis survival (MbT). The potential of a library of compounds as selective anti - tuberculosis drugs was investigated. Docking was first conducted using MoE to determine the effectiveness of the compounds. Molecular docking studies followed by MD simulation studies (total of 500 ns) in combination with free energy calculations grade the ligands in terms of their binding affinities. In the ligand bound state of the CS, MD simulations revealed a change from stretched to bended motional shift in loop L19. The RMSF analysis also revealed this flexibility, which was confirmed by visual inspection of L19 at various time intervals during the experiment. It appears that ZF1(-25.43Kcal/mol) and ZF2 (-22.04Kcal/mol) form hbonds and have a high binding energy in the active region of protein. Residues wise distribution of binding energy reveals that Arg144, Trp4, Thr6, and L19 amino acid residues are engaged in binding of CS with inhibitors. In summary, the findings suggest that compounds ZF1 and ZF2 may be more effective and selective anti-TB agents than currently available drugs. Also the role of L19, mediated by alpha H9 and alpha H5 in the retention of ligand inside the active pocket, through the formation of lid was also revealed. This knowledge will aid in the discovery of drugs that are potent CS inhibitors. More experimental research and a better understanding of the structure-activity relationship could aid in the development of possible candidates with better CS inhibition. Communicated by Ramaswamy H. Sarma