http://orcid.org/0000-0002-4821-1654
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Abstract
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.
| Abbreviations | ||
| ADME | = | Absorption, Distribution, Metabolism, And Excretion |
| BCG | = | Bacillus Calmette-Guerin |
| CNS | = | Central nervous system |
| DOTS | = | Directly observed treatment, short course |
| ED | = | Essential dynamics |
| HIV | = | Human immunodeficiency virus |
| HK | = | Histidine kinase |
| HOA | = | Human oral absorption |
| HTVS | = | High throughput virtual screening |
| IRRI | = | Irritation |
| MD | = | Molecular dynamics |
| MDR | = | Multidrug resistant |
| MTB | = | Mycobacterium tuberculosis |
| MUT | = | Mutagenicity |
| MW | = | Molecular weight |
| PHOA | = | Percentage of human oral absorption |
| REP | = | Reproductive development |
| Rg | = | Radius of gyration |
| RMSD | = | Root mean square deviation |
| RMSF | = | Root mean square fluctuation |
| RO5 | = | Lipinski’s rule of five |
| RR | = | Response regulator |
| SP | = | Standard precision |
| SPG | = | Standard precision glide |
| TB | = | Tuberculosis |
| TCS | = | Two-component regulatory system |
| TDR | = | Totally drug-resistant |
| TUMO | = | Tumorigenicity |
| WHO | = | World health organization |
| XDR | = | Extensively drug-resistant |
| XP | = | Extra precision |
Communicated by Ramaswamy H. Sarma
Acknowledgements
NK and RK are thankful to UGC and CSIR, respectively, for their fellowships.
Disclosure statement
No potential conflict of interest was reported by the author(s)