基于结构的分析揭示了齐墩果酸是麦芽寡糖转移酶的新型潜在抑制剂。
Structure-based and Analysis Reveals Asiatic Acid as Novel Potential Inhibitor of Maltosyl Transferase.
机构信息
Department of Biosciences, Integral University, Lucknow-226026, India.
Department of Biotechnology, Parul Institute of Applied Sciences and Centre of Research for Development, Parul University, Vadodara, Gujarat-391760, India.
出版信息
Curr Comput Aided Drug Des. 2022;18(3):213-227. doi: 10.2174/1573409918666220623105908.
AIMS
The present study aimed to search for novel potent inhibitor(s) against the recently discovered maltosyltransferase (GlgE) target of M.tb.
BACKGROUND
GlgE belongs to an α-amylase family and catalyzes the elongation of cytosolic branched α-glucan. Inactivation of M.tb. GlgE results in DNA damage and rapid death of M.tb. due to the accumulation of a toxic altosyl donor, maltose-1-phosphate (M1P), suggesting that GlgE is an intriguing target for inhibitor design.
METHODS
1000 natural compounds were compiled from public databases and literature through virtual screening, of which 25 compounds were found to satisfy all drug-likeness properties and ADME/ toxicity criteria, followed by molecular docking with GlgE. Compound(s) showing the lowest binding energy was further subjected to molecular dynamics simulation (MDS) and in vitro analysis.
RESULTS
Molecular docking analysis allowed the selection of 5 compounds withsignificant binding affinity to GlgE targets. Amongst these compounds, asiatic acid exhibited the lowest binding energy (-12.61 kcal/mol). The results of 20-ns MDS showed that asiatic acid formed a stable complex with GlgE. Additionally, asiatic acid exhibited in vitro anti-mycobacterial activity against M.tb. H37Ra, M. bovis BCG, and M. smegmatis strains.
CONCLUSION
The study reveals asiatic acid as a promising anti-mycobacterial agent that might emerge as a novel natural anti-TB lead molecule in the future.
目的
本研究旨在寻找新型有效的抑制剂来抑制最近发现的结核分枝杆菌麦芽基转移酶（GlgE）靶标。
背景
GlgE 属于α-淀粉酶家族，可催化胞质支链α-葡聚糖的延伸。结核分枝杆菌 GlgE 的失活会导致 DNA 损伤和结核分枝杆菌的快速死亡，这是由于有毒的麦芽基供体麦芽-1-磷酸（M1P）的积累，这表明 GlgE 是抑制剂设计的一个有趣的靶点。
方法
通过虚拟筛选，从公共数据库和文献中编译了 1000 种天然化合物，其中 25 种化合物被发现满足所有药物样性质和 ADME/毒性标准，然后与 GlgE 进行分子对接。与 GlgE 靶标具有最低结合能的化合物进一步进行分子动力学模拟（MDS）和体外分析。
结果
分子对接分析允许选择 5 种与 GlgE 靶标具有显著结合亲和力的化合物。在这些化合物中，齐墩果酸表现出最低的结合能（-12.61 kcal/mol）。20-ns MDS 的结果表明，齐墩果酸与 GlgE 形成了稳定的复合物。此外，齐墩果酸在体外对结核分枝杆菌 H37Ra、牛分枝杆菌 BCG 和耻垢分枝杆菌菌株表现出抗分枝杆菌活性。
结论
本研究揭示了齐墩果酸作为一种有前途的抗分枝杆菌药物，可能成为未来新型天然抗结核先导分子。
Zotero 插件