Discovery of an EP300 Inhibitor using Structure-based Virtual Screening and Bioactivity Evaluation

Title:Discovery of an EP300 Inhibitor using Structure-based Virtual Screening and Bioactivity Evaluation

Volume: 30 Issue: 25

Author(s): Dabo Pan*, Yaxuan Huang, Dewen Jiang, Yonghao Zhang, Mingkai Wu, Minzhen Han*Xiaojie Jin*

Affiliation:

• 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

• College of Pharmacy, Gansu University of Chinese Medicine, Lanzhou 730000, China

Abstract:

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 (ΔG_nonpolar). 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.

Cite this article as:

Pan Dabo*, Huang Yaxuan, Jiang Dewen, Zhang Yonghao, Wu Mingkai, Han Minzhen*, Jin Xiaojie*, Discovery of an EP300 Inhibitor using Structure-based Virtual Screening and Bioactivity Evaluation, Current Pharmaceutical Design 2024; 30 (25) . https://dx.doi.org/10.2174/0113816128298051240529113313