Alanzi Abdullah R
Department of Pharmacognosy, College of Pharmacy, King Saud University, Riyadh, Saudi Arabia.
Int J Mycobacteriol. 2023 Jul-Sep;12(3):332-344. doi: 10.4103/ijmy.ijmy_149_23.
Mycobacterium tuberculosis is a bacterium that has historically had a substantial impact on human health. Despite advances in understanding and management of tuberculosis (TB), the disease remains a crucial problem that necessitates ongoing work to discover effective drugs, minimize transmission, and improve global health outcomes.
The purpose of this study is to use molecular docking and absorption, distribution, metabolism, excretion, and toxicity (ADMET) analyses to explore the molecular interactions of different proteins that are involved in mycolic acid biosynthesis (HadAB, InhA, KasA, FabD, and beta-ketoacyl-acyl carrier protein synthase III) of M. tuberculosis with Demospongiae metabolites. The docking findings were evaluated using the glide gscore, and the top 10 compounds docked against each protein receptor were chosen. Furthermore, the selected compounds underwent ADMET analysis, indicating that they have the potential for therapeutic development.
Among the selected compounds, makaluvamine G showed the highest binding affinity against HadAB, psammaplysin E showed highest binding affinity against InhA, pseudotheonamide D showed the highest binding affinity against KasA protein, dinordehydrobatzelladine B showed the highest binding affinity against FabD, and nagelamide X showed the highest binding affinity against beta-ketoacyl-acyl carrier protein synthase III. Additionally, molecular mechanics generalized born surface area (MM-GBSA) binding free energy and molecular dynamics simulations were used to support the docking investigations.
The results of the study suggest that these compounds may eventually be used to treat TB. However, computer validations were included in this study, and more in vitro research is required to turn these prospective inhibitors into clinical drugs.
结核分枝杆菌是一种历史上对人类健康产生重大影响的细菌。尽管在结核病（TB）的理解和管理方面取得了进展，但该疾病仍然是一个关键问题，需要持续开展工作以发现有效药物、减少传播并改善全球健康状况。
本研究的目的是利用分子对接以及吸收、分布、代谢、排泄和毒性（ADMET）分析，探索参与结核分枝杆菌分枝菌酸生物合成（HadAB、InhA、KasA、FabD和β-酮酰基-酰基载体蛋白合酶III）的不同蛋白质与海绵代谢产物之间的分子相互作用。使用Glide gscore评估对接结果，并选择针对每种蛋白质受体对接的前10种化合物。此外，对所选化合物进行ADMET分析，表明它们具有治疗开发的潜力。
在所选化合物中，马卡鲁胺G对HadAB显示出最高的结合亲和力，沙马普利辛E对InhA显示出最高的结合亲和力，假鞘氨醇酰胺D对KasA蛋白显示出最高的结合亲和力，双去氢巴泽拉定B对FabD显示出最高的结合亲和力，纳格拉酰胺X对β-酮酰基-酰基载体蛋白合酶III显示出最高的结合亲和力。此外还使用分子力学广义玻恩表面积（MM-GBSA）结合自由能和分子动力学模拟来支持对接研究。
研究结果表明这些化合物最终可能用于治疗结核病。然而，本研究纳入了计算机验证，需要更多的体外研究才能将这些潜在抑制剂转化为临床药物。
