Journal
MOLECULES
Volume 23, Issue 12, Pages -Publisher
MDPI
DOI: 10.3390/molecules23123282
Keywords
activity cliff; activity landscape plotter; epigenetics; docking; drug discovery; d-tools; molecular dynamics; epi-polypharmacology; SmART; structure-activity relationships
Funding
- School of Chemistry of the Universidad Nacional Autonoma de Mexico (UNAM)
- Programa de Apoyo a Proyectos de Investigacion e Innovacion Tecnologica (PAPIIT), UNAM [IA203718]
- Consejo Nacional de Ciencia y Tecnologia (CONACyT) [282785]
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In this work we discuss the insights from activity landscape, docking and molecular dynamics towards the understanding of the structure-activity relationships of dual inhibitors of major epigenetic targets: lysine methyltransferase (G9a) and DNA methyltranferase 1 (DNMT1). The study was based on a novel data set of 50 published compounds with reported experimental activity for both targets. The activity landscape analysis revealed the presence of activity cliffs, e.g., pairs of compounds with high structure similarity but large activity differences. Activity cliffs were further rationalized at the molecular level by means of molecular docking and dynamics simulations that led to the identification of interactions with key residues involved in the dual activity or selectivity with the epigenetic targets.
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