基于结构的虚拟筛选和生物活性评估发现 EP300 抑制剂。
Discovery of an EP300 Inhibitor using Structure-based Virtual Screening and Bioactivity Evaluation.
机构信息
Department of Medical Technology, Qiandongnan Vocational and Technical College for Nationalities, Kaili 556000, China.
Department of Pharmacy, The Second Affiliated Hospital of Guizhou Medical University, Guizhou Medical University, Kaili 556000, China.
出版信息
Curr Pharm Des. 2024;30(25):1985-1994. doi: 10.2174/0113816128298051240529113313.
BACKGROUND
EP300 (E1A binding protein p300) played a significant role in serial diseases such as cancer, neurodegenerative disease. Therefore, it became a significant target.
METHODS
Targeting EP300 discovery of a novel drug to alleviate these diseases. In this paper, 17 candidate compounds were obtained using a structure-based virtual screening approach, 4449-0460, with an IC of 5.89 ± 2.08 uM, which was identified by the EP300 bioactivity test. 4449-0460 consisted of three rings. The middle benzene ring connected the 5-ethylideneimidazolidine-2,4-dione group and the 3-F-Phenylmethoxy group.
RESULTS
Furthermore, the interaction mechanism between 4449-0460 and EP300 was explored by combining molecular dynamics (MD) simulations and binding free energy calculation methods.
CONCLUSION
The binding free energy of EP300 with 4449-0460 was -10.93 kcal/mol, and mainly came from the nonpolar energy term (ΔG). Pro1074, Phe1075, Val1079, Leu1084, and Val1138 were the key residues in EP300/4449-0460 binding with more -1 kcal/mol energy contribution. 4449-0460 was a promising inhibitor targeting EP300, which had implications for the development of drugs for EP300-related diseases.
背景
EP300（E1A 结合蛋白 p300）在癌症、神经退行性疾病等一系列疾病中发挥着重要作用。因此，它成为了一个重要的靶点。
方法
针对 EP300 发现一种新型药物来缓解这些疾病。在本文中，使用基于结构的虚拟筛选方法获得了 17 种候选化合物，IC 为 5.89 ± 2.08 μM，通过 EP300 生物活性测试鉴定为 4449-0460。4449-0460 由三个环组成。中间苯环连接 5-亚乙基咪唑烷-2,4-二酮基团和 3-F-苯甲氧基基团。
结果
此外，通过结合分子动力学（MD）模拟和结合自由能计算方法，探讨了 4449-0460 与 EP300 之间的相互作用机制。
结论
EP300 与 4449-0460 的结合自由能为-10.93 kcal/mol，主要来自非极性能量项（ΔG）。Pro1074、Phe1075、Val1079、Leu1084 和 Val1138 是 EP300/4449-0460 结合的关键残基，其能量贡献超过-1 kcal/mol。4449-0460 是一种有前途的针对 EP300 的抑制剂，这对开发与 EP300 相关的疾病药物具有重要意义。
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