Kumar Niranjan, Srivastava Rakesh, Mongre Raj Kumar, Mishra Chandra Bhushan, Kumar Amit, Khatoon Rosy, Banerjee Atanu, Ashraf-Uz-Zaman Md, Singh Harpreet, Lynn Andrew M, Lee Myeong-Sok, Prakash Amresh
School of Computational and Integrative Sciences, Jawaharlal Nehru University, New Delhi, India.
Molecular Cancer Biology Laboratory, Cellular Heterogeneity Research Center, Department of Biosystem, Sookmyung Women's University, Seoul, South Korea.
Front Microbiol. 2022 May 6;13:818714. doi: 10.3389/fmicb.2022.818714. eCollection 2022.
Mycolic acids are the key constituents of mycobacterial cell wall, which protect the bacteria from antibiotic susceptibility, helping to subvert and escape from the host immune system. Thus, the enzymes involved in regulating and biosynthesis of mycolic acids can be explored as potential drug targets to kill (Mtb). Herein, Kyoto Encyclopedia of Genes and Genomes is used to understand the fatty acid metabolism signaling pathway and integrative computational approach to identify the novel lead molecules against the mtFabH (β-ketoacyl-acyl carrier protein synthase III), the key regulatory enzyme of the mycolic acid pathway. The structure-based virtual screening of antimycobacterial compounds from ChEMBL library against mtFabH results in the selection of 10 lead molecules. Molecular binding and drug-likeness properties of lead molecules compared with mtFabH inhibitor suggest that only two compounds, ChEMBL414848 (C1) and ChEMBL363794 (C2), may be explored as potential lead molecules. However, the spatial stability and binding free energy estimation of thiolactomycin (TLM) and compounds C1 and C2 with mtFabH using molecular dynamics simulation, followed by molecular mechanics Poisson-Boltzmann surface area (MM/PBSA) indicate the better activity of C2 (ΔG = -14.18 kcal/mol) as compared with TLM (ΔG = -9.21 kcal/mol) and C1 (ΔG = -13.50 kcal/mol). Thus, compound C1 may be explored as promising drug candidate for the structure-based drug designing of mtFabH inhibitors in the therapy of Mtb.
分枝菌酸是分枝杆菌细胞壁的关键成分，可保护细菌免受抗生素影响，有助于其破坏并逃离宿主免疫系统。因此，参与分枝菌酸调控和生物合成的酶可作为杀死结核分枝杆菌（Mtb）的潜在药物靶点进行研究。在此，利用京都基因与基因组百科全书来了解脂肪酸代谢信号通路，并采用综合计算方法来识别针对mtFabH（β-酮酰基-酰基载体蛋白合成酶III）的新型先导分子，mtFabH是分枝菌酸途径的关键调控酶。对来自ChEMBL库的抗分枝杆菌化合物针对mtFabH进行基于结构的虚拟筛选，结果选出了10个先导分子。将先导分子与mtFabH抑制剂的分子结合和类药性质进行比较，结果表明只有两种化合物，即ChEMBL414848（C1）和ChEMBL363794（C2），可作为潜在的先导分子进行研究。然而，使用分子动力学模拟，随后采用分子力学泊松-玻尔兹曼表面积法（MM/PBSA）对硫霉素（TLM）以及化合物C1和C2与mtFabH的空间稳定性和结合自由能进行估算，结果表明与TLM（ΔG = -9.21 kcal/mol）和C1（ΔG = -13.50 kcal/mol）相比，C2的活性更好（ΔG = -14.18 kcal/mol）。因此，在结核分枝杆菌治疗中，化合物C1可作为基于结构的mtFabH抑制剂药物设计的有前景的候选药物进行研究。
