Diversity and Chemical Space Characterization of Inhibitors of the Epigenetic Target G9a: A Chemoinformatics Approach

G9a is a histone-lysinemethyltransferase that performs the mono-and dimethylation of lysine 9 at histone 3 of the nucleosome. It belongsto the SET PKMT family, and its methylations are related to promoterrepression and activation. G9a is a promising epigenetic target. Despitethe fact that there are several G9a inhibitors under development,there are no compounds in clinical use due to adverse in vivo ADMET(absorption, distribution, metabolism, excretion, and toxicity) issues.The goal of this study is to discuss the exploration, characterization,and analysis of the chemical space of 409 G9a inhibitors reportedin a large public database. Exploring the chemical space of the inhibitorsled to the quantification of their structural diversity based on molecularscaffolds and structural fingerprints of different designs. As partof the analysis, the G9a inhibitors were compared with commerciallibraries focused on epigenetic targets. The findings of this workwill help in the development of, in a follow-up study, predictivemodels to identify G9a inhibitors. This study also points out therelevance of screening commercial libraries to expand the epigeneticrelevant chemical space, in particular, G9a inhibitors.

Automated summary

This study explores, characterizes, and analyzes the chemical space of 409 G9a inhibitors reported in a large public database. It quantifies the structural diversity of G9a inhibitors and compares them with commercial libraries focused on epigenetic targets. The findings will contribute to the development of predictive models for identifying G9a inhibitors and highlight the importance of screening commercial libraries to expand the relevant chemical space.