文献类型：期刊文献

英文题名：Discovery of an EP300 Inhibitor using Structure-based Virtual Screening and Bioactivity Evaluation

作者：Pan, Dabo[1,2];Huang, Yaxuan[1];Jiang, Dewen[1];Zhang, Yonghao[1];Wu, Mingkai[1];Han, Minzhen[2];Jin, Xiaojie[3]

第一作者：Pan, Dabo

通信作者：Pan, DB[1];Pan, DB[2];Han, MZ[2];Jin, XJ[3]

机构：[1]Qiandongnan Vocat & Tech Coll Nationalities, Dept Med Technol, Kaili 556000, Peoples R China;[2]Guizhou Med Univ, Second Affiliated Hosp, Dept Pharm, Kaili 556000, Peoples R China;[3]Gansu Univ Chinese Med, Coll Pharm, Lanzhou 730000, Peoples R China

第一机构：Qiandongnan Vocat & Tech Coll Nationalities, Dept Med Technol, Kaili 556000, Peoples R China

通信机构：[1]corresponding author), Qiandongnan Vocat & Tech Coll Nationalities, Dept Med Technol, Kaili 556000, Peoples R China;[2]corresponding author), Guizhou Med Univ, Second Affiliated Hosp, Dept Pharm, Kaili 556000, Peoples R China;[3]corresponding author), Gansu Univ Chinese Med, Coll Pharm, Lanzhou 730000, Peoples R China.|[1073501e14fb35863569f]甘肃中医药大学药学院（西北中藏药协同创新中心办公室）;[10735]甘肃中医药大学;

年份：2024

卷号：30

期号：25

起止页码：1985

外文期刊名：CURRENT PHARMACEUTICAL DESIGN

收录：;Scopus(收录号：2-s2.0-85200268874);WOS:【SCI-EXPANDED(收录号:WOS:001239140200001)】；

基金：This work was supported by the Project of National Natural Science Foundation of China (81803347), the Scientific and Technological Founding of Guizhou Province (QKHZC [2020]4Y087and QKHZC[2020]YB289), University Science and Technology Innovation Team of Department of Education of Guizhou Province(QJJ[2023]099), the Scientific and Technological Founding of Qiandongnan (QDNKHJC[2023]10) and High-level Innovative Talents Program of Guizhou Province (QQCC [2022]201708)

语种：英文

外文关键词：EP300; inhibitor; structure-based virtual screening; binding free energy calculation; molecular dynamics simulations; disease

摘要：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 IC50 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 (Delta Gnonpolar). 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.