Structure-based virtual screening, molecular dynamics simulation and MM-PBSA toward identifying the inhibitors for two-component regulatory system protein NarL of <i>Mycobacterium Tuberculosis</i>
Creators: name: Niranjan Kumar
name: Srivastava, Rakesh
name: Amresh Prakash
name: Andrew. M. Lynn
Publisher: name: Taylor & Francis
Year: 2019
Subjects: subject: Biochemistry
subject: Genetics
subject: FOS: Biological sciences
subject: FOS: Biological sciences
subject: Molecular Biology
subject: Pharmacology
subject: Biotechnology
subject: 39999 Chemical Sciences not elsewhere classified
subject: FOS: Chemical sciences
subject: FOS: Chemical sciences
subject: 69999 Biological Sciences not elsewhere classified
subject: 80699 Information Systems not elsewhere classified
subject: FOS: Computer and information sciences
subject: FOS: Computer and information sciences
subject: Cancer
subject: 110309 Infectious Diseases
subject: FOS: Health sciences
subject: FOS: Health sciences
subject: 60506 Virology
subject: Computational Biology

description: The nitrate/nitrite response regulatory protein NarL belongs to the two-component regulatory system of <i>Mycobacterium tuberculosis</i> (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. AbbreviationsADMEAbsorption, Distribution, Metabolism, And ExcretionBCGBacillus Calmette-GuerinCNSCentral nervous systemDOTSDirectly observed treatment, short courseEDEssential dynamicsHIVHuman immunodeficiency virusHKHistidine kinaseHOAHuman oral absorptionHTVSHigh throughput virtual screeningIRRIIrritationMDMolecular dynamicsMDRMultidrug resistantMTB<i>Mycobacterium tuberculosis</i>MUTMutagenicityMWMolecular weightPHOAPercentage of human oral absorptionREPReproductive developmentRgRadius of gyrationRMSDRoot mean square deviationRMSFRoot mean square fluctuationRO5Lipinski’s rule of fiveRRResponse regulatorSPStandard precisionSPGStandard precision glideTBTuberculosisTCSTwo-component regulatory systemTDRTotally drug-resistantTUMOTumorigenicityWHOWorld health organizationXDRExtensively drug-resistantXPExtra precision Absorption, Distribution, Metabolism, And Excretion Bacillus Calmette-Guerin Central nervous system Directly observed treatment, short course Essential dynamics Human immunodeficiency virus Histidine kinase Human oral absorption High throughput virtual screening Irritation Molecular dynamics Multidrug resistant <i>Mycobacterium tuberculosis</i> Mutagenicity Molecular weight Percentage of human oral absorption Reproductive development Radius of gyration Root mean square deviation Root mean square fluctuation Lipinski’s rule of five Response regulator Standard precision Standard precision glide Tuberculosis Two-component regulatory system Totally drug-resistant Tumorigenicity World health organization Extensively drug-resistant Extra precision Communicated by Ramaswamy H. Sarma