Adnan Md, Jeon Byeong-Bae, Chowdhury Md Helal Uddin, Oh Ki-Kwang, Das Tuhin, Chy Md Nazim Uddin, Cho Dong-Ha
Department of Bio-Health Convergence, College of Biomedical Science, Kangwon National University, Chuncheon 24341, Korea.
Ethnobotany and Pharmacognosy Lab, Department of Botany, University of Chittagong, Chattogram 4331, Bangladesh.
Life (Basel). 2022 Feb 13;12(2):277. doi: 10.3390/life12020277.
L. (CS) is widely used to treat diabetic complications in south-east Asia, specifically in traditional Chinese medicine. This study intends to explain the molecular mechanism of how chemical constituents of CS interrelate with different signaling pathways and receptors involved in T2DM. GC-MS was employed to identify the chemical compounds from the methanol extract of CS wood (MECSW). Lipinski's rule of five was applied, and 33 bioactive constituents have been screened from the CS extract. After that, 124 common targets and 26 compounds associated with T2DM were identified by mining several public databases. Protein-protein interactions and compound-target network were constructed using the STRING database and Cytoscape tool. Protein-protein interactions were identified in 121 interconnected nodes active in T2DM and peroxisome proliferator-activated receptor gamma (PPARG) as key target receptors. Furthermore, pathway compound target (PCT) analysis using the merger algorithm plugin of Cytoscape revealed 121 nodes from common T2DM targets, 33 nodes from MECSW compounds and 9 nodes of the KEGG pathway. Moreover, network topology analysis determined "Fisetin tetramethyl ether" as the key chemical compound. The DAVID online tool determined seven signaling receptors, among which PPARG was found most significant in T2DM progression. Gene ontology and KEGG pathway analysis implied the involvement of nine pathways, and the peroxisome proliferator-activated receptor (PPAR) pathway was selected as the hub signaling pathway. Finally, molecular docking and quantum chemistry analysis confirmed the strong binding affinity and reactive chemical nature of fisetin tetramethyl ether with target receptors exceeding that of the conventional drug (metformin), PPARs agonist (rosiglitazone) and co-crystallized ligands, indicating that fisetin could be a potential drug of choice in T2DM management. This study depicts the interrelationship of the bioactive compounds of MECSW with the T2DM-associated signaling pathways and target receptors. It also proposes a more pharmaceutically effective substance, fisetin tetramethyl ether, over the standard drug that activates PPARG protein in the PPAR signaling pathway of T2DM.
在东南亚，尤其是在传统中医中，黄连广泛用于治疗糖尿病并发症。本研究旨在解释黄连化学成分与2型糖尿病（T2DM）相关的不同信号通路和受体之间相互关联的分子机制。采用气相色谱 - 质谱联用（GC-MS）法从黄连木甲醇提取物（MECSW）中鉴定化合物。应用了Lipinski的五规则，从黄连提取物中筛选出33种生物活性成分。之后，通过挖掘多个公共数据库，确定了124个常见靶点和26种与T2DM相关的化合物。使用STRING数据库和Cytoscape工具构建了蛋白质 - 蛋白质相互作用和化合物 - 靶点网络。在121个与T2DM相关的相互连接节点中鉴定出蛋白质 - 蛋白质相互作用，其中过氧化物酶体增殖物激活受体γ（PPARG）作为关键靶受体。此外，使用Cytoscape的合并算法插件进行的通路化合物靶点（PCT）分析显示，来自常见T2DM靶点的121个节点、来自MECSW化合物的33个节点和KEGG通路的9个节点。此外，网络拓扑分析确定“非瑟酮四甲醚”为关键化合物。DAVID在线工具确定了七种信号受体，其中PPARG在T2DM进展中最为显著。基因本体论和KEGG通路分析表明涉及九条通路，过氧化物酶体增殖物激活受体（PPAR）通路被选为核心信号通路。最后，分子对接和量子化学分析证实非瑟酮四甲醚与靶受体的强结合亲和力和反应性化学性质超过了传统药物（二甲双胍）、PPARs激动剂（罗格列酮）和共结晶配体，表明非瑟酮可能是T2DM治疗中一种潜在的首选药物。本研究描述了MECSW生物活性化合物与T2DM相关信号通路和靶受体之间的相互关系。它还提出了一种比在T2DM的PPAR信号通路中激活PPARG蛋白的标准药物在药学上更有效的物质，即非瑟酮四甲醚。
