基于分子动力学模拟和自由能计算的 NHWD-870 与含溴结构域蛋白 4 的结合机制。
The binding mechanism of NHWD-870 to bromodomain-containing protein 4 based on molecular dynamics simulations and free energy calculation.
机构信息
State Key Laboratory of Biotherapy/Collaborative Innovation Center of Biotherapy and Cancer Center, West China Hospital of Sichuan University, Chengdu, Sichuan 610041, China.
College of Chemistry, MOE Key Laboratory of Green Chemistry and Technology, Sichuan University, Chengdu, Sichuan 610064, China.
出版信息
Phys Chem Chem Phys. 2022 Feb 23;24(8):5125-5137. doi: 10.1039/d1cp05490b.
Bromodomain and extra-terminal (BET) proteins (BRD2, BRD3, BRD4, and BRDT) are epigenetic readers with tandem bromodomains. Small-molecule inhibitors of BET proteins are a promising treatment strategy against cancer. For example, NHWD-870 can inhibit BRD4 (BD1 + BD2). Presently, structural data on NHWD-870 bound BRD4 remain lacking. Herein, we investigate the interactions between NHWD-870 and BRD4 (BD1 and BD2) molecular docking, molecular dynamics simulation, and binding free energy calculations. NHWD-870 showed a similar binding affinity for BD1 and BD2 of BRD4. Binding free energy calculations for the / conformations of NHWD-870 suggest that the chiral centre of NHWD-870 may confer similar roles upon the and conformations for binding with BRD4, facilitating the identification of novel BRD4 inhibitors.
溴结构域和末端（BET）蛋白（BRD2、BRD3、BRD4 和 BRDT）是具有串联溴结构域的表观遗传读蛋白。BET 蛋白的小分子抑制剂是一种有前途的癌症治疗策略。例如，NHWD-870 可以抑制 BRD4（BD1+BD2）。目前，NHWD-870 结合 BRD4 的结构数据仍然缺乏。在此，我们通过分子对接、分子动力学模拟和结合自由能计算研究了 NHWD-870 与 BRD4（BD1 和 BD2）之间的相互作用。NHWD-870 对 BRD4 的 BD1 和 BD2 表现出相似的结合亲和力。NHWD-870 的 / 构象的结合自由能计算表明，NHWD-870 的手性中心可能在与 BRD4 结合时赋予 / 构象相似的作用，从而促进新型 BRD4 抑制剂的鉴定。
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