Activity Landscape and Molecular Modeling to Explore the SAR of Dual Epigenetic Inhibitors: A Focus on G9a and DNMT1
1
Medicinal Chemistry Laboratory, University of Veracruz, Agustín de Iturbide Esq. Carmen Serdan, 91700 Veracruz, Mexico
2
Department of Pharmacy, School of Chemistry, National Autonomous University of Mexico, 04510 Mexico City, Mexico
*
Author to whom correspondence should be addressed.
Academic Editor: Simone Brogi
Molecules 2018, 23(12), 3282; https://doi.org/10.3390/molecules23123282
Received: 24 November 2018 / Revised: 9 December 2018 / Accepted: 10 December 2018 / Published: 11 December 2018
(This article belongs to the Special Issue Computational Approaches for Drug Discovery)
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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Keywords:
activity cliff; activity landscape plotter; epigenetics; docking; drug discovery; d-tools; molecular dynamics; epi-polypharmacology; SmART; structure-activity relationships
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MDPI and ACS Style
López-López, E.; Prieto-Martínez, F.D.; Medina-Franco, J.L. Activity Landscape and Molecular Modeling to Explore the SAR of Dual Epigenetic Inhibitors: A Focus on G9a and DNMT1. Molecules 2018, 23, 3282.
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