Structure-based virtual screening, molecular dynamics simulation and MM-PBSA toward identifying the inhibitors for two-component regulatory system protein NarL of Mycobacterium Tuberculosis

The nitrate/nitrite response regulatory protein NarL belongs to the two-component regulatory system of Mycobacterium tuberculosis (MTB), plays a crucial role in anaerobic survival of mycobacteria in host. The absence of this protein in humans, makes it an attractive drug target for MTB treatment. However, the specific drug molecules targeting NarL are yet to be identified. In this study, we identified the promising drug candidates using structure based virtual screening of compounds from chemical libraries (ChEMBL and ZINC), followed by the extensive physicochemical properties analyses and molecular dynamics (MD) simulation. As the initial results, we obtained 4,754 bioactive compounds from ChEMBL having anti-tuberculosis activity which is finally narrowed down to the best 10 hits. A similar approach was applied to search for structurally similar compounds from ZINC data, corresponding to the top hits obtained from ChEMBL. Our collective results show that two compounds, ChEMBL509609 (Gscore - 5.054 kcal/mol, Xscore - 6.47 kcal/mol) and ZINC01843143 (Gscore - 5.114 kcal/mol, Xscore - 6.46 kcal/mol) having the best docking score and ADMET profile. The structural stability and dynamics of lead molecules at active site of NarL were examined using MD simulation and the binding free energies were estimated with MM-PBSA. Essential dynamics and MM-PBSA demonstrated that NarL-ChEMBL509609 complex remains the most stable during simulation of 100 ns with the higher binding free energy which may be a suitable candidate for further experimental analysis.