PDF(Pubmed)
Abstract：
The protein Bcl-2, well-known for its anti-apoptotic properties, has been implicated in cancer pathogenesis. Identifying the primary gene responsible for promoting improved cell survival and development has provided compelling evidence for preventing cellular death in the progression of malignancies. Numerous research studies have provided evidence that the abundance of Bcl-2 is higher in malignant cells, suggesting that suppressing Bcl-2 expression could be a viable therapeutic approach for cancer treatment. In this study, we acquired a compound collection using a database that includes constituents from Traditional Chinese Medicine (TCM). Initially, we established a pharmacophore model and utilized it to search the TCM database for potential compounds. Compounds with a fitness score exceeding 0.75 were selected for further analysis. The Absorption, Distribution, Metabolism, Excretion, and Toxicity (ADMET) analysis identified six compounds with favorable therapeutic characteristics. The compounds that successfully passed the initial screening process based on the pharmacodynamic model were subjected to further evaluation. Extra-precision (XP) docking was employed to identify the compounds with the most favorable XP docking scores. Further analysis using the Molecular Mechanics Generalized Born Surface Area (MM-GBSA) method to calculate the overall free binding energy. The binding energy between the prospective ligand molecule and the target protein Bcl-2 was assessed by a 100 ns molecular dynamics simulation for curcumin and Epigallocatechin gallate (EGCG). The findings of this investigation demonstrate the identification of a molecular structure that effectively inhibits the functionality of the Bcl-2 when bound to the ligand EGCG. Consequently, this finding presents a novel avenue for the development of pharmaceuticals capable of effectively addressing both inflammatory and tumorous conditions.
摘要：
Bcl-2蛋白以其抗凋亡特性而闻名，与癌症的发病机制有关。鉴定负责促进细胞存活和发育改善的主要基因已经为防止恶性肿瘤进展中的细胞死亡提供了令人信服的证据。大量的研究提供了证据，表明在恶性细胞中Bcl-2的丰度更高，提示抑制Bcl-2表达可能是一种可行的癌症治疗方法。在这项研究中,我们使用包含中药（TCM）成分的数据库获得了化合物集合。最初，我们建立了药效基团模型,并利用该模型在TCM数据库中搜索潜在化合物.选择适应性评分超过0.75的化合物用于进一步分析。吸收,Distribution,代谢，排泄,和毒性(ADMET)分析确定了具有良好治疗特性的六种化合物。对成功通过基于药效学模型的初始筛选过程的化合物进行进一步评价。采用超精密(XP)对接来鉴定具有最有利的XP对接得分的化合物。使用分子力学广义玻恩表面积(MM-GBSA)方法进一步分析以计算总自由结合能。通过100ns姜黄素和表没食子儿茶素没食子酸酯（EGCG）的分子动力学模拟评估了预期配体分子与靶蛋白Bcl-2之间的结合能。这项研究的发现证明了当与配体EGCG结合时有效抑制Bcl-2功能的分子结构的鉴定。因此,这一发现为开发能够有效解决炎症和肿瘤疾病的药物提供了新的途径。
