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Current Pharmaceutical Design

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ISSN (Print): 1381-6128
ISSN (Online): 1873-4286

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Research Article

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

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

Volume 30, Issue 25, 2024

Published on: 03 June, 2024

Page: [1985 - 1994] Pages: 10

DOI: 10.2174/0113816128298051240529113313

Price: $65

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 (ΔGnonpolar). 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.

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