TITLE:
Expanding the Boundaries of the Chemical Space of DNA Methyltransferase 1 Modulators
AUTHORS:
Massyel S. Martínez-Cortés, Diana L. Prado-Romero, José L. Medina-Franco
KEYWORDS:
Chemical Multiverse, Chemoinformatics, Epigenetics, Pharmacophore Hypothesis, Small Molecules
JOURNAL NAME:
Computational Molecular Bioscience,
Vol.14 No.1,
February
19,
2024
ABSTRACT: DNA methyltransferase 1 (DNMT1), one of the main epigenetic targets, is involved in the duplication of the DNA methylation pattern during replication, and it is essential for proper mammalian development. Small molecule DNMT1 modulators are attractive for biochemical epigenetic studies and have the potential to become drugs. So far, more than five hundred small molecules have been reported as DNMT1 inhibitors. However, only a limited number of DNMT1 activators have been disclosed because, at least in part, DNMT1 activators are typically regarded as negative data in virtual screening campaigns or optimization projects. This manuscript aims to report the chemical structures and biological activity of small molecules that increase the enzymatic activity of DNMT1. Results of the biochemical experimental assays are discussed. It was found that small molecule activators have a large variety of chemical scaffolds but share pharmacophore features. Visual analysis of the chemical space and multiverse based on molecular fingertips supported that activators are structurally diverse. This is the first report of eight small molecules that increase the enzymatic activity of DNMT1 by more than 400% in an enzymatic-based assay. The outcome warrants further investigation of the epigenetic activity of the compounds in a counter-screen assay, e.g., cell-based and in vivo context.