Preprint Article Version 1 This version is not peer-reviewed

Activity Landscape and Molecular Modeling to Explore the SAR of Dual Epigenetic Inhibitors: A Focus on G9a and DNMT1

Version 1 : Received: 24 November 2018 / Approved: 26 November 2018 / Online: 26 November 2018 (07:14:05 CET)

How to cite: 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. Preprints 2018, 2018110574 (doi: 10.20944/preprints201811.0574.v1). 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. Preprints 2018, 2018110574 (doi: 10.20944/preprints201811.0574.v1).

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 metiltransferase (G9a) and DNA metiltranferase 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 difference. 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.

Subject Areas

activity cliff; activity landscape plotter; epigenetics; docking; drug discovery; D-tools; molecular dynamics; Epi-polypharmacology; SmART; structure-activity relationships

Readers' Comments and Ratings (0)

Leave a public comment
Send a private comment to the author(s)
Views 0
Downloads 0
Comments 0
Metrics 0


×
Alerts
Notify me about updates to this article or when a peer-reviewed version is published.