Alkhathami Ali G, Alshahrani Mohammad Y, Asiri Mohammed, Wahab Shadma
Department of Clinical Laboratory Sciences, College of Applied Medical Sciences, King Khalid University, P.O. Box 61413, Abha, 9088, Saudi Arabia.
Department of Pharmacognosy, College of Pharmacy, King Khalid University, Abha, 62529, Saudi Arabia.
Sci Rep. 2025 Sep 26;15(1):33029. doi: 10.1038/s41598-025-99901-0.
B-cell lymphoma 2 (Bcl-2) is a crucial regulatory protein involved in the control of apoptosis. Its overexpression in cancer cells facilitates evasion of programmed cell death, contributing to their survival and resistance to chemotherapy. Consequently, Bcl-2 has emerged as a promising drug target in cancer therapy. There is still ongoing research to find potential drug molecules that target Bcl-2 with higher potency, selectivity, and safety profile. This study was carried out by conducting a virtual screening of phytoconstituents from the IMPPAT database that could potentially inhibit the aberrant activity of Bcl-2. We first excluded compounds that did not abide by the Lipinski rule of five based on their physicochemical properties. We also calculated binding affinities, applied PAINS filters, and performed ADMET and PASS analyses, as well as interaction analyses, to identify compounds that were predicted to be safe and effective. Finally, two compounds, Daturilinol and Withametelin B, were selected because of their high binding and selective binding to Bcl-2. We analyzed these compounds in terms of time evolution by employing molecular dynamics simulation (MDS), principal component analysis (PCA), free energy landscape (FEL), and MM/PBSA. Consequently, we suggest that Daturilinol and Withametelin B could be further investigated in vitro and in vivo for therapeutic development against cancer.
B细胞淋巴瘤2（Bcl-2）是一种参与细胞凋亡调控的关键调节蛋白。其在癌细胞中的过度表达有助于逃避程序性细胞死亡，从而促进癌细胞的存活及对化疗的抗性。因此，Bcl-2已成为癌症治疗中一个有前景的药物靶点。目前仍在进行研究，以寻找能够更高效、更具选择性且安全性更高地靶向Bcl-2的潜在药物分子。本研究通过对IMPPAT数据库中的植物成分进行虚拟筛选来开展，这些植物成分可能抑制Bcl-2的异常活性。我们首先根据其物理化学性质排除了不符合Lipinski五规则的化合物。我们还计算了结合亲和力，应用了PAINS过滤器，并进行了ADMET和PASS分析以及相互作用分析，以识别预测为安全有效的化合物。最后，由于Daturilinol和Withametelin B与Bcl-2具有高结合力和选择性结合，因此选择了这两种化合物。我们通过分子动力学模拟（MDS）、主成分分析（PCA）、自由能景观（FEL）和MM/PBSA对这些化合物进行了时间演化分析。因此，我们建议可以在体外和体内进一步研究Daturilinol和Withametelin B，以开发抗癌治疗方法。
