Zhou L, Zhao Z, Xiong F, Chen Y, Sun Y
School of Pharmacy, Wannan Medical College, Wuhu 241002, China.
Provincial Engineering Laboratory for Screening and Reevaluation of Active Compounds of Herbal Medicines in Southern Anhui, Wuhu 241002, China.
Nan Fang Yi Ke Da Xue Xue Bao. 2022 Jan 20;42(1):71-77. doi: 10.12122/j.issn.1673-4254.2022.01.08.
To identify the target genes mediating anti-tumor effect of sesquiterpenoids from Cryptoporus volvatus and explore the possible mechanism using molecular docking and molecular dynamics simulation.
Based on the chemical structure of sesquiterpenes from , we explored the online reverse target finding websites PharmMapper, SEA, Target Hunter and related literature for preliminary prediction of possible anti-tumor targets. Discovery Studio 4.0 (Libdock function) and Maestro 12.3 were used to connect sesquiterpenes with the possible targets, and the potential targets were selected according to the scores. The interaction between the sesquiterpenes and the targets were analyzed using 2D interaction diagram, and the influence of different sesquiterpene skeletons on their activity was inferred based on their activity measurements in experiment. Kinetic simulation was performed for front-end protein sequence (1UNQ) of the Akt (protein kinase B) and for the complex formed by 1UNQ and compound 4 (which had the best cytotoxic activity ) in its optimal conformation, and the root mean square deviation (RMSD) value and root mean square float (RMSF) value of the complex and 1UNQ were measured to evaluate the stability of the binding of compound 4 to the target.
The sesquiterpenes showed optimal binding with 1UNQ. Analysis of 2D interaction diagram suggested that the hydrogen bonding and electrostatic force were the most important forces mediating the interaction between the sesquiterpenes and 1UNQ. Analysis of the optimal 3D conformation showed that for different sesquiterpenes, a slight change of the molecular framework produced a steric hindrance effect and caused changes in their bioactivity. Kinetic simulation showed that the complex formed by compound 4 and1UNQ had a lower RMSD than the target pure protein sequence, indicating that compound could stably bind to 1UNQ. The anti-tumor effect of the sesquiterpenoids from was associated with their ability to cause Lys-144 acetylation, which blocks Akt binding to the downstream PIP3 and thus affects the proliferation of tumor cells.
1UNQ is the target of sesquiterpenoids from , which affects the proliferation of tumor cells by acetylating Lys-14.
鉴定介导茯苓倍半萜抗肿瘤作用的靶基因，并利用分子对接和分子动力学模拟探索其可能的作用机制。
基于茯苓倍半萜的化学结构，利用在线反向靶点预测网站PharmMapper、SEA、Target Hunter及相关文献对可能的抗肿瘤靶点进行初步预测。使用Discovery Studio 4.0（Libdock功能）和Maestro 12.3将倍半萜与可能的靶点进行对接，并根据得分筛选潜在靶点。利用二维相互作用图分析倍半萜与靶点之间的相互作用，并根据实验中它们的活性测定推断不同倍半萜骨架对其活性的影响。对Akt（蛋白激酶B）的前端蛋白序列（1UNQ）以及由1UNQ与具有最佳细胞毒性活性的化合物4形成的复合物在其最佳构象下进行动力学模拟，测量复合物和1UNQ的均方根偏差（RMSD）值和均方根波动（RMSF）值，以评估化合物4与靶点结合的稳定性。
倍半萜与1UNQ显示出最佳结合。二维相互作用图分析表明，氢键和静电力是介导倍半萜与1UNQ相互作用的最重要作用力。对最佳三维构象的分析表明，对于不同的倍半萜，分子框架的轻微变化会产生空间位阻效应并导致其生物活性发生变化。动力学模拟表明，化合物4与1UNQ形成的复合物的RMSD低于目标纯蛋白序列，表明化合物4能够稳定地与1UNQ结合。茯苓倍半萜的抗肿瘤作用与其引起Lys-144乙酰化的能力有关，这会阻止Akt与下游PIP3结合，从而影响肿瘤细胞的增殖。
1UNQ是茯苓倍半萜的靶点，其通过乙酰化Lys-14影响肿瘤细胞的增殖。
