Binding selectivity of inhibitors toward the first over the second bromodomain of BRD4: theoretical insights from free energy calculations and multiple short molecular dynamics simulations.
Binding selectivity of inhibitors toward the first over the second bromodomain of BRD4: theoretical insights from free energy calculations and multiple short molecular dynamics simulations.
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抑制剂对 BRD4 第一个溴结构域相对于第二个溴结构域的结合选择性：来自自由能计算和多个短分子动力学模拟的理论见解
DOI：
10.1039/d0ra09469b
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发表时间：
2020-12-24
期刊：
影响因子：
3.9
通讯作者：
Zhang L
中科院分区：
文献类型：
--
作者：
Wang Y;Wu S;Wang L;Yang Z;Zhao J;Zhang L
含溴结构域蛋白4（Bromodomain-containing protein 4，BRD 4）在介导基因转录中发挥重要作用，与癌症和非癌症疾病如急性心力衰竭和炎症性疾病有关。在这项工作中，多个短分子动力学（MSMD）模拟集成与分子力学广义玻恩表面积（MM-GBSA）的方法来破译三个抑制剂8 NS，82 Y，和837对两个域BD 1和BD 2的BRD 4的结合选择性。结果表明，焓效应在抑制剂对BD 1和BD 2的选择性鉴定中起关键作用，确定8 NS对BD 2的选择性优于BD 1，而82 Y和837更有利地结合BD 1而不是BD 2。基于残基的自由能分解方法被用来计算一个通道-残基相互作用光谱和揭示的贡献单独的残基结合选择性。结果确定了六种常见的残基，（P82，P375），（V87，V380），（L92，L385），（L94，L387），（N140，N433），和（I146，V439）单独属于（BD 1，BD 2），并产生抑制剂与BD 1和BD 2的相当大的结合差异，表明这些残基在抑制剂对BRD 4的BD 1和BD 2的结合选择性中起关键作用。因此，这些结果提供了有用的动力学信息和结构亲和关系的发展高度选择性抑制剂针对BD 1和BD 2的BRD 4。
Bromodomain-containing protein 4 (BRD4) plays an important role in mediating gene transcription involved in cancers and non-cancer diseases such as acute heart failure and inflammatory diseases. In this work, multiple short molecular dynamics (MSMD) simulations are integrated with a molecular mechanics generalized Born surface area (MM-GBSA) approach to decipher binding selectivity of three inhibitors 8NS, 82Y, and 837 toward two domains BD1 and BD2 of BRD4. The results demonstrate that the enthalpy effects play critical roles in selectivity identification of inhibitors toward BD1 and BD2, determining that 8NS has better selectivity toward BD2 than BD1, while 82Y and 837 more favorably bind to BD1 than BD2. A residue-based free-energy decomposition method was used to calculate an inhibitor–residue interaction spectrum and unveil contributions of separate residues to binding selectivity. The results identify six common residues, containing (P82, P375), (V87, V380), (L92, L385), (L94, L387), (N140, N433), and (I146, V439) individually belonging to (BD1, BD2) of BRD4, and yield a considerable binding difference of inhibitors to BD1 and BD2, suggesting that these residues play key roles in binding selectivity of inhibitors toward BD1 and BD2 of BRD4. Therefore, these results provide useful dynamics information and a structure affinity relationship for the development of highly selective inhibitors targeting BD1 and BD2 of BRD4.
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影响因子：
37.3
作者：
Donati B;Lorenzini E;Ciarrocchi A
通讯作者：
Ciarrocchi A
影响因子：
5
作者：
Chen, Jianzhong;Yin, Baohua;Sun, Haibo
通讯作者：
Sun, Haibo
从绝对结合自由能计算中的配体选择性预测。
影响因子：
15
作者：
Aldeghi M;Heifetz A;Bodkin MJ;Knapp S;Biggin PC
通讯作者：
Biggin PC
相互作用熵：高效可靠计算蛋白质-配体结合自由能的新范式
影响因子：
15
作者：
Duan, Lili;Liu, Xiao;Zhang, John Z. H.
通讯作者：
Zhang, John Z. H.
影响因子：
2.9
作者：
Bas, Delphine C.;Rogers, David M.;Jensen, Jan H.
通讯作者：
Jensen, Jan H.