López-López E, Rabal O, Oyarzabal J, Medina-Franco JL. 2020. Towards the Understanding of the Activity of G9a Inhibitors: An Activity Landscape and Molecular Modeling Approach JOURNAL OF COMPUTER-AIDED MOLECULAR DESIGN, 34, 659-669.
López-López E, Rabal O, Oyarzabal J, Medina-Franco JL. 2020. Towards the Understanding of the Activity of G9a Inhibitors: An Activity Landscape and Molecular Modeling Approach JOURNAL OF COMPUTER-AIDED MOLECULAR DESIGN, 34, 659-669.
López-López E, Rabal O, Oyarzabal J, Medina-Franco JL. 2020. Towards the Understanding of the Activity of G9a Inhibitors: An Activity Landscape and Molecular Modeling Approach JOURNAL OF COMPUTER-AIDED MOLECULAR DESIGN, 34, 659-669.
López-López E, Rabal O, Oyarzabal J, Medina-Franco JL. 2020. Towards the Understanding of the Activity of G9a Inhibitors: An Activity Landscape and Molecular Modeling Approach JOURNAL OF COMPUTER-AIDED MOLECULAR DESIGN, 34, 659-669.
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.
Chemistry and Materials Science, Medicinal Chemistry
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