Next Article in Journal
The Potential Use of Plant Natural Products and Plant Extracts with Antioxidant Properties for the Prevention/Treatment of Neurodegenerative Diseases: In Vitro, In Vivo and Clinical Trials
Next Article in Special Issue
Toward of Safer Phenylbutazone Derivatives by Exploration of Toxicity Mechanism
Previous Article in Journal
Purification and Functional Characterization of the C-Terminal Domain of the β-Actin-Binding Protein AIM1 In Vitro
Previous Article in Special Issue
Classical QSAR and Docking Simulation of 4-Pyridone Derivatives for Their Antimalarial Activity
Article Menu
Issue 12 (December) cover image

Export Article

Open AccessArticle
Molecules 2018, 23(12), 3282; https://doi.org/10.3390/molecules23123282

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
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)
  |  
PDF [15240 KB, uploaded 11 December 2018]
  |  

Abstract

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. View Full-Text
Keywords: activity cliff; activity landscape plotter; epigenetics; docking; drug discovery; d-tools; molecular dynamics; epi-polypharmacology; SmART; structure-activity relationships activity cliff; activity landscape plotter; epigenetics; docking; drug discovery; d-tools; molecular dynamics; epi-polypharmacology; SmART; structure-activity relationships
Figures

Graphical abstract

This is an open access article distributed under the Creative Commons Attribution License which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited (CC BY 4.0).

Supplementary material

SciFeed

Share & Cite This Article

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.

Show more citation formats Show less citations formats

Note that from the first issue of 2016, MDPI journals use article numbers instead of page numbers. See further details here.

Related Articles

Article Metrics

Article Access Statistics

1

Comments

[Return to top]
Molecules EISSN 1420-3049 Published by MDPI AG, Basel, Switzerland RSS E-Mail Table of Contents Alert
Back to Top