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

Area of Science:

• Medicinal Chemistry
• Drug Discovery
• Computational Chemistry

Background:

• EP300 (E1A binding protein p300) is implicated in various diseases, including cancer and neurodegenerative disorders.
• Its significant role makes EP300 a crucial target for therapeutic intervention.

Purpose of the Study:

• To discover novel drug candidates targeting EP300 for disease treatment.
• To identify and characterize potent inhibitors of EP300 activity.

Main Methods:

• Structure-based virtual screening was employed to identify candidate compounds.
• EP300 bioactivity testing was performed, yielding compound 4449-0460 with an IC50 of 5.89 ± 2.08 uM.
• Molecular dynamics simulations and binding free energy calculations were used to explore the interaction mechanism.

Main Results:

• Compound 4449-0460, featuring a three-ring structure, demonstrated significant EP300 inhibitory activity.
• The binding free energy between EP300 and 4449-0460 was calculated to be -10.93 kcal/mol.
• Key residues (Pro1074, Phe1075, Val1079, Leu1084, Val1138) were identified as major contributors to the binding energy.

Conclusions:

• Compound 4449-0460 is a promising inhibitor targeting EP300.
• The detailed interaction mechanism provides insights for further drug development.
• This research has significant implications for developing novel therapeutics for EP300-associated diseases.