School of Computational & Integrative Sciences, Jawaharlal Nehru University, New Delhi, India.
Amity Institute of Integrative Sciences and Health, Amity University, Haryana, Gurgaon, India.
J Biomol Struct Dyn. 2020 Jul;38(11):3396-3410. doi: 10.1080/07391102.2019.1657499. Epub 2019 Aug 26.
The nitrate/nitrite response regulatory protein NarL belongs to the two-component regulatory system of (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 resistantMTBMUTMutagenicityMWMolecular 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 precisionCommunicated by Ramaswamy H. Sarma.
硝酸盐/亚硝酸盐反应调节蛋白 NarL 属于 （MTB） 的双组分调节系统，在分枝杆菌在宿主中的厌氧生存中起着至关重要的作用。由于人类缺乏这种蛋白质，使其成为治疗 MTB 的一个有吸引力的药物靶点。然而，针对 NarL 的特定药物分子尚未被确定。在这项研究中，我们使用化学文库（ChEMBL 和 ZINC）中的化合物进行基于结构的虚拟筛选，随后进行广泛的物理化学性质分析和分子动力学（MD）模拟，从而确定了有前途的药物候选物。作为初步结果，我们从具有抗结核活性的 ChEMBL 中获得了 4754 种生物活性化合物，最终将其缩小到最佳的 10 个命中化合物。采用类似的方法从 ZINC 数据中搜索与从 ChEMBL 获得的最佳命中化合物结构相似的化合物。我们的综合结果表明，两种化合物，ChEMBL509609（Gscore-5.054kcal/mol，Xscore-6.47kcal/mol）和 ZINC01843143（Gscore-5.114kcal/mol，Xscore-6.46kcal/mol）具有最佳的对接评分和 ADMET 特性。使用 MD 模拟研究了配体在 NarL 活性部位的结构稳定性和动力学，并用 MM-PBSA 估算了结合自由能。基本动力学和 MM-PBSA 表明，在 100ns 的模拟过程中，NarL-ChEMBL509609 复合物保持最稳定，结合自由能较高，这可能是进一步实验分析的合适候选物。缩写ADME 吸收、分布、代谢和排泄卡介苗中枢神经系统DOTSDirect 观察治疗，短期疗程EDEDissential dynamicsHIV 人类免疫缺陷病毒HKHistidine kinaseHOAHuman 口腔吸收HTVSHigh throughput virtual screeningIRRIIrritationMD 分子动力学MDR 多药耐药MTBMUT 突变性MW 分子量PHOAPercentage of human oral absorptionREP 生殖发育Rg 回转半径RMSDRoot mean square deviationRMSFRoot mean square fluctuationRO5Lipinski 的规则五RRResponse 调节剂SP 标准精度SPG 标准精度滑行TBTuberculosisTCSTwo 组分调节系统TDRTotally 耐药TUMOTumorigenicity世卫组织世界卫生组织XDRExtensively 耐药XPExtra 精度由 Ramaswamy H. Sarma 传达。
