Current advances on the development of BET inhibitors: insights from computational methods
Fernando D Prieto-Martínez1, José L Medina-Franco1
1Department of Pharmacy, School of Chemistry, National Autonomous University of Mexico, Mexico City, Mexico.
Abstract:
Epigenetics was coined almost 70 years ago for the description of heritable phenotype without altering DNA sequences. Research on the field has uncovered significant roles of such mechanisms, that account for the biogenesis of several diseases. Further studies have led the way for drug development which targets epi-enzymes, mainly for cancer treatment. Of the numerous epi-targets involved with histone acetylation, bromodomains have captured the spotlight of drug discovery focused on novel therapies. However, due to high sequence identity, the development of potent and selective inhibitors poses a significant challenge. Herein, we discuss recent computational developments on BET inhibitors and other methods that may be applied for drug discovery in general. As a proof-of-concept, we discuss a virtual screening to identify novel BET inhibitors based on coumarin derivatives. From public data, we identified putative structure-activity relationships of coumarin scaffold and propose R-group modifications for BET selectivity. Results showed that the optimization and design of novel coumarins could be further explored.
Insights
Epigenetic drug discovery targets bromodomains (BET) for cancer therapy. Computational methods, including virtual screening of coumarin derivatives, show promise for developing selective BET inhibitors.
Area of Science:
- Epigenetics and Molecular Biology
- Medicinal Chemistry
- Computational Drug Discovery
Background:
- Epigenetics describes heritable traits without DNA sequence changes, crucial in disease development.
- Targeting epigenetic enzymes (epi-enzymes) is a key strategy for novel therapeutics, especially in oncology.
- Bromodomains, particularly BET proteins, are significant epigenetic targets, but developing selective inhibitors is challenging due to sequence homology.
Purpose of the Study:
- To explore computational developments for epigenetic drug discovery.
- To present a proof-of-concept virtual screening for novel BET inhibitors.
- To investigate coumarin derivatives as potential BET inhibitors and identify structure-activity relationships for selectivity.
Main Methods:
- Review of recent computational advancements in epigenetic drug discovery.
- Virtual screening of coumarin derivatives against BET targets.
- Analysis of public data to establish structure-activity relationships for coumarin scaffolds.
- Proposal of R-group modifications to enhance BET selectivity.
Main Results:
- Identification of potential structure-activity relationships for coumarin derivatives as BET inhibitors.
- Demonstration of virtual screening as a viable method for discovering novel epigenetic modulators.
- Highlighting the potential for optimizing coumarin scaffolds for enhanced BET selectivity.
Conclusions:
- Computational approaches, including virtual screening, are valuable for identifying selective epigenetic inhibitors.
- Coumarin derivatives represent a promising scaffold for developing novel BET inhibitors.
- Further optimization and design of coumarin-based compounds warrant exploration for therapeutic applications.
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