Wang Xue-Song, Zheng Qing-Chuan
Laboratory of Theoretical and Computational Chemistry, Institute of Theoretical Chemistry, International Joint Research Laboratory of Nano-Micro Architecture Chemistry, Jilin University, Changchun 130023, People's Republic of China.
Key Laboratory for Molecular Enzymology and Engineering of the Ministry of Education, Jilin University, Changchun 130012, People's Republic of China; Laboratory of Theoretical and Computational Chemistry, Institute of Theoretical Chemistry, International Joint Research Laboratory of Nano-Micro Architecture Chemistry, Jilin University, Changchun 130023, People's Republic of China.
Bioorg Med Chem. 2018 Feb 1;26(3):712-720. doi: 10.1016/j.bmc.2017.12.040. Epub 2017 Dec 26.
The CBP (CREB (cAMP responsive element binding protein) binding protein) bromodomain (BRD) could recognize and bind with acetyl K382 of human tumor suppressor protein p53 which the mutation of encoding gene might cause human cancers. CBP-BRD serves as a promising drug target for several disease pathways and a series of effective drug have been discovered. In this study, molecular dynamics (MD) simulations and molecular mechanics generalized born surface area (MM-GB/SA) approaches were performed to investigate the different binding modes between five inhibitors with CBP-BRD. Based on the energy and conformation analyses, a potent core fragment is chosen to act as the starting point for new inhibitor design by means of LUDI and rational drug design approaches. Then, T.E.S.T and molinspirition were applied to evaluate oral bioavailability and drug promiscuity of the new molecules. These results shed light on the idea for further inhibitor design.
CBP（CREB（环磷酸腺苷反应元件结合蛋白）结合蛋白）的溴结构域（BRD）能够识别并结合人类肿瘤抑制蛋白p53的乙酰化K382位点，而p53编码基因的突变可能引发人类癌症。CBP-BRD是多种疾病途径中颇具潜力的药物靶点，并且已经发现了一系列有效的药物。在本研究中，通过分子动力学（MD）模拟和分子力学广义Born表面面积（MM-GB/SA）方法，研究了五种抑制剂与CBP-BRD之间不同的结合模式。基于能量和构象分析，选择一个有效的核心片段作为通过LUDI和合理药物设计方法进行新抑制剂设计的起点。然后，应用T.E.S.T和molinspirition评估新分子的口服生物利用度和药物混杂性。这些结果为进一步的抑制剂设计提供了思路。
