Najafi Vahideh, Yoosefian Mehdi, Hassani Zahra
Department of Chemistry, Graduate University of Advanced Technology, Kerman, Iran.
Department of New Materials, Institute of Science, High Technology and Environmental Sciences, Graduate University of Advanced Technology, Kerman, Iran.
Cell Biochem Funct. 2023 Jan;41(1):58-66. doi: 10.1002/cbf.3760. Epub 2022 Oct 18.
Cancer cells are resistant to apoptosis and this is one of the most obvious symptoms of cancer in humans. One of the most exciting strategies for treating cancer is to design regulators that increase cell death and stop cell growth. Members of the BCL-2 family of proteins play an important role in the regulation of apoptosis. In this study, an attempt was made to improve the performance of one of the anticancer drugs by designing new analogs of venetoclax (VNT). For this purpose, molecular docking studies were performed to determine the best binding state of VNT and its newly designed derivatives at the protein-binding site to estimate the binding energy. The best analog in terms of free energy was VNT-12 with the lowest energy (-12.15 kcal/mol). Finally, to investigate the inhibitory effect of the compounds on BCL-2 protein, molecular dynamics simulation was used, and by performing the relevant analyses during the simulation, it was observed that the newly designed ligand had better performance in inhibiting BCL-2 protein compared to VNT.
癌细胞对细胞凋亡具有抗性，这是人类癌症最明显的症状之一。治疗癌症最令人兴奋的策略之一是设计能增加细胞死亡并阻止细胞生长的调节剂。BCL-2蛋白家族成员在细胞凋亡的调节中起重要作用。在本研究中，试图通过设计维奈托克（VNT）的新类似物来提高一种抗癌药物的性能。为此，进行了分子对接研究，以确定VNT及其新设计的衍生物在蛋白质结合位点的最佳结合状态，从而估算结合能。就自由能而言，最佳类似物是能量最低（-12.15千卡/摩尔）的VNT-12。最后，为了研究这些化合物对BCL-2蛋白的抑制作用，使用了分子动力学模拟，并且通过在模拟过程中进行相关分析，观察到新设计的配体在抑制BCL-2蛋白方面比VNT具有更好的性能。
