细胞凋亡受 BCL-2 家族调控，该家族包括抗凋亡蛋白和促凋亡蛋白（Bax、Bok、Bak 等）。这些蛋白质通常以二聚体形式相互作用并充当细胞凋亡开关。抗凋亡蛋白（例如 BCL-2）可阻断这些促凋亡蛋白的功能。必须抑制促凋亡和抗凋亡蛋白-蛋白相互作用，以防止肿瘤细胞逃避凋亡。该方法已用于通过天然和合成化合物抑制 BCL-2 来开发抗癌药物。含金属化合物长期以来被用作人类癌症患者的药物，顺铂是此类药物的第一个候选药物。然而，药物设计需要更多地关注金属配合物。我们详细研究了 BCL-2 蛋白的 X 射线晶体结构，并鉴定了具有两个溶剂可及性较低的位点的疏水性。根据化合物的疏水性，从剑桥晶体学数据库中筛选出 74 种具有 X 射线晶体学特征的生物活性（包括抗癌活性）的有机金属化合物。为了进行测试，使用分子对接来确定哪种化合物对 BCL-2 蛋白最有效。有机金属化合物 (苯)-氯-(1-{[(9H-芴-2-基)亚氨基]甲基}萘-2-醇)-钌(2), (1-((1,1'-联苯)) -4-基)-2,3,4,5-四甲基环戊二烯基)-氯-(4,4'-二甲基-2,2'-联吡啶)-六氟磷酸铑 (37), (μ-1,1'-(丁烷-1,4-二基)双(3-氧基-2-甲基吡啶-4(1H)-酮))-二氯-双(五甲基环戊二烯基)-二铑四水合物 (46), (μ-1,1 '-(丁烷-1,4-二基)双(3-氧基-2-甲基吡啶-4(1H)-酮))-二氯-双(五甲基-环戊二烯基)-二铱(47)等被发现本研究中的重要化合物。使用复合物的赫什菲尔德表面分析来识别不同类型的复合物相互作用的能力。进行 NCI 图是为了了解复杂氨基酸和活性位点氨基酸之间相互作用的性质。进行了 DFT 研究来检查所选配合物的稳定性和化学反应性。通过这项研究，我们发现了一种合适的疏水性先导抗癌有机金属药物，它可以与 BCL-2 溶剂不易接近的疏水位点结合。版权所有 © 2023 Elsevier Ltd。保留所有权利。

Apoptosis is regulated by the BCL-2 family, which includes the anti-apoptotic and pro-apoptotic proteins (Bax, Bok, Bak, etc.). These proteins often interact in dimers and act as apoptotic switches. Anti-apoptotic proteins, such as BCL-2, block the functions of these pro-apoptotic proteins. The pro-apoptotic and anti-apoptotic protein-protein interactions must be inhibited to prevent tumor cells from escaping apoptosis. This method has been used to develop anticancer drugs by inhibiting BCL-2 with both natural and synthetic compounds. Metal-containing compounds were used as pharmaceuticals for human cancer patients for a long time, and cisplatin was the first candidate of this class. Drug design, however, needs to pay more attention to metal complexes. We have studied the X-ray crystal structure of the BCL-2 protein in detail and identified the hydrophobic nature of the site with two less solvent-accessible sites. Based on the hydrophobic nature of the compounds, 74 organometallic compounds with X-ray crystallographically characterized bioactivity (including anticancer activity) were selected from the Cambridge crystallographic database. For testing, molecular docking was used to determine which compound was most effective against the BCL-2 protein. Organometallic compounds (benzene)-chloro-(1-{[(9H-fluoren-2-yl)imino]methyl}naphthalen-2-olato)-ruthenium (2), (1-((1,1'-biphenyl)-4-yl)-2,3,4,5-tetramethylcyclopentadienyl)-chloro-(4,4'-dimethyl-2,2'-bipyridine)-rhodium hexafluorophosphate (37), (μ-1,1'-(butane-1,4-diyl)bis(3-oxy-2-methylpyridin-4(1H)-one))-dichloro-bis(pentamethyl-cyclopentadienyl)-di-rhodium tetrahydrate (46), (μ-1,1'-(butane-1,4-diyl)bis(3-oxy-2-methylpyridin-4(1H)-one))-dichloro-bis(pentamethyl-cyclopentadienyl)-di-iridium (47) etc are found to be important compounds in this study. The capability of different types of complex interactions was identified using Hirshfeld surface analysis of the complexes. A NCI plot was conducted to understand the nature of the interaction between complex amino acids and active-site amino acids. A DFT study was conducted to examine the stability and chemical reactivity of the selected complexes. Using this study, one suitable hydrophobic lead anti-cancer organometallic pharmaceutical was found that binds at the less solvent-accessible hydrophobic site of BCL-2.Copyright © 2023 Elsevier Ltd. All rights reserved.