Kb Suma, Kumari Ankita, Shetty Diya, Fernandes Everlyse, Dv Chethan, Jays Judy, Murahari Manikanta
Department of Pharmaceutical Chemistry, Faculty of Pharmacy, M.S. Ramaiah University of Applied Sciences, Bangalore, India.
Department of Pharmaceutical Chemistry, Faculty of Pharmacy, M.S. Ramaiah University of Applied Sciences, Bangalore, India.
J Mol Graph Model. 2020 Dec;101:107718. doi: 10.1016/j.jmgm.2020.107718. Epub 2020 Aug 21.
Cell wall of mycobacterium acts as a primary interface which helps in the regulation of important functions and also aids to pathogenicity and virulence of the organism, making it a crucial target for drug discovery. Decaprenylphosphoryl-d-ribose 2'-epimerase (DprE), is important for the growth and survival of Mycobacterium tuberculosis. DprE1 is a donor of arabinose sugars which helps in the formation of cell wall components-lipoarabinomannan and arabinogalactan through Decaprenyl-phosphoryl d-arabinose (DPA) pathway. In our study, we have chosen Azaindole derivatives as DprE1 inhibitors which possess non-covalent property. TBA7371 (azaindole derivative, non-covalent inhibitor) is currently in first phase of clinical trials as DprE1 inhibitor. Azaindoles have been found to be equally potent against drug-sensitive and isoniazid/rifampin-resistant strains. Hence, azaindoles are an attractive class for further optimization as potential DprE1 inhibitors for TB. Structure-based pharmacophore model was generated to investigate the compounds with similar molecular features. Compounds having a good fitness score and pharmacophoric features were compared with the molecules in clinical trial and were proceeded for molecular docking studies to identify the binding affinity of the compounds with target protein DprE1. Energy based calculations using Prime MM-GBSA of Schrodinger was further executed to examine free binding energy of the ligands. The prediction of pharmacokinetic parameters (ADME) plays an important role to identify safe and potent molecules which may further have potential to become drug candidates. Induced-fit docking approach and Molecular Dynamics integrated with Prime MM-GBSA calculations of both hit compounds has further confirmed the binding affinity and stability. All the results obtained from our study were interpreted and compared with DprE1 inhibitor in clinical trials. Study identified ZINC000170252277 as a potential hit compound for further biological evaluation as DprE1 inhibitor.
分枝杆菌的细胞壁作为主要界面，有助于调节重要功能，也有助于该生物体的致病性和毒力，使其成为药物研发的关键靶点。癸异戊二烯基磷酸 -d-核糖2'-表异构酶（DprE）对结核分枝杆菌的生长和存活至关重要。DprE1是阿拉伯糖的供体，通过癸异戊二烯基 - 磷酸 -d-阿拉伯糖（DPA）途径有助于细胞壁成分 - 脂阿拉伯甘露聚糖和阿拉伯半乳聚糖的形成。在我们的研究中，我们选择氮杂吲哚衍生物作为具有非共价性质的DprE1抑制剂。TBA7371（氮杂吲哚衍生物，非共价抑制剂）目前作为DprE1抑制剂处于临床试验的第一阶段。已发现氮杂吲哚对药物敏感和异烟肼/利福平耐药菌株同样有效。因此，氮杂吲哚作为潜在的结核DprE1抑制剂，是一个有吸引力的进一步优化类别。生成基于结构的药效团模型以研究具有相似分子特征的化合物。将具有良好拟合分数和药效团特征的化合物与临床试验中的分子进行比较，并进行分子对接研究以确定化合物与靶蛋白DprE1的结合亲和力。进一步使用薛定谔的Prime MM - GBSA进行基于能量的计算，以检查配体的自由结合能。药代动力学参数（ADME）的预测对于识别可能进一步有潜力成为候选药物的安全有效分子起着重要作用。诱导契合对接方法以及与两种命中化合物的Prime MM - GBSA计算相结合的分子动力学进一步证实了结合亲和力和稳定性。我们研究获得的所有结果都进行了解释，并与临床试验中的DprE1抑制剂进行了比较。研究确定ZINC000170252277作为潜在的命中化合物，用于作为DprE1抑制剂进行进一步的生物学评估。
