【摘要】 溴结构域蛋白4在细胞周期调节中至关重要,已成为治疗各种癌症的潜在靶标.溴结构域蛋白4包含两个溴结构域,即BD1和BD2.研究表明,选择性地抑制BD1或BD2可能提供更有效的治疗方案.因此,了解抑制剂对BD1和BD2结合的选择性机制对于开发BD1和BD2的高选择性抑制剂至关重要.本文利用多副本分子动力学模拟研究了抑制剂SG3-179、GSK778和GSK620对BD1和BD2的结合选择性.结果显示,BD1比BD2具有更强的结构灵活性,而且BD1和BD2表现出不同的内部动力学.对自由能景观的分析表明,BD1和BD2的构象分布存在明显的差异.结合自由能预测表明,熵变、静电相互作用和范德华相互作用是SG3-179、GSK778和GSK620对BD1和BD2选择性结合的关键因素.单个残基能量贡献的计算表明,(BD1,BD2)中的残基(W81,W374)、(P82,P375)、(Q85,K378)、(V87,V380)、(L92,L385)、(N93,G386)、(L94,L387)、(C136,C429)、(N140,N433)、(K141,P434)、(D144,H437)和(I146,V439)在SG3-179、GSK778和GSK620与BD1和BD2的结合中产生明显的能量差异,它们可以作为开发针对BD1或BD2的高选择性抑制剂的有效靶点.相关信息可为提高抑制剂对BD1和BD2的选择性提供重要的理论指导.更多还原

【Abstract】 Bromodomain-containing protein 4(BRD4) is critical in cell cycle regulation and has emerged as a potential target for treatment of various cancers.BRD4 contains two bromodomains,namely BD1 and BD2.Research suggests that selectively inhibiting BD1 or BD2 may provide more effective treatment options.Therefore,understanding the selective mechanism of inhibitor binding to BD1 and BD2 is essential for development of high selective inhibitors to BD1 and BD2.Multiple replica molecular dynamics(MRMD) simulations are utilized to investigate the binding selectivity of inhibitors SG3-179,GSK778,and GSK620 for BD1 and BD2.The results show that BD1 has stronger structural flexibility than BD2,moreover BD1 and BD2 exhibit different internal dynamics.The analyses of free energy landscapes reveal significant differences in the conformational distribution of BD1 and BD2.Binding free energy predictions suggest that entropy changes,electrostatic interactions,and van der Waals interactions are key factors in the selective binding of BD1and BD2 by SG3-179,GSK778,and GSK620.The calculations of the energy contributions of individual residues demonstrate that residues(W81,W374),(P82,P375),(Q85,K378),(V87,V380),(L92,L385),(N93,G386),(L94,L387),(C136,C429),(N140,N433),(K141,P434),(D144,H437) and(1146,V439) corresponding to(BD1,BD2) generate significant energy difference in binding of SG3-179,GSK778,and GSK620 to BD1 and BD2,and they can serve as effective targets for development of high selective inhibitors against BD1 or BD2.The related information may provide significant theoretical guidance for improving the selectivity of inhibitors for BD1 and BD2.更多还原