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Towards the understanding of the activity of G9a inhibitors: an activity landscape and molecular modeling approach.
López-López, Edgar; Rabal, Obdulia; Oyarzabal, Julen; Medina-Franco, José L.
Afiliación
  • López-López E; Department of Pharmacy, School of Chemistry, National Autonomous University of Mexico, 04510, Mexico City, Mexico.
  • Rabal O; Small Molecule Discovery Platform, Molecular Therapeutics Program, Center for Applied Medical Research, CIMA, University of Navarra, Pio XII, 55, 31008, Pamplona, Spain.
  • Oyarzabal J; Small Molecule Discovery Platform, Molecular Therapeutics Program, Center for Applied Medical Research, CIMA, University of Navarra, Pio XII, 55, 31008, Pamplona, Spain.
  • Medina-Franco JL; Department of Pharmacy, School of Chemistry, National Autonomous University of Mexico, 04510, Mexico City, Mexico. medinajl@unam.mx.
J Comput Aided Mol Des ; 34(6): 659-669, 2020 06.
Article en En | MEDLINE | ID: mdl-32060676
In this work, we analyze the structure-activity relationships (SAR) of epigenetic inhibitors (lysine mimetics) against lysine methyltransferase (G9a or EHMT2) using a combined activity landscape, molecular docking and molecular dynamics approach. The study was based on a set of 251 G9a inhibitors with reported experimental activity. The activity landscape analysis rapidly led to the identification of activity cliffs, scaffolds hops and other active an inactive molecules with distinct SAR. Structure-based analysis of activity cliffs, scaffold hops and other selected active and inactive G9a inhibitors by means of docking followed by molecular dynamics simulations led to the identification of interactions with key residues involved in activity against G9a, for instance with ASP 1083, LEU 1086, ASP 1088, TYR 1154 and PHE 1158. The outcome of this work is expected to further advance the development of G9a inhibitors.
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Relación Estructura-Actividad / N-Metiltransferasa de Histona-Lisina / Inhibidores Enzimáticos / Antígenos de Histocompatibilidad Límite: Humans Idioma: En Revista: J Comput Aided Mol Des Asunto de la revista: BIOLOGIA MOLECULAR / ENGENHARIA BIOMEDICA Año: 2020 Tipo del documento: Article País de afiliación: México Pais de publicación: Países Bajos
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Relación Estructura-Actividad / N-Metiltransferasa de Histona-Lisina / Inhibidores Enzimáticos / Antígenos de Histocompatibilidad Límite: Humans Idioma: En Revista: J Comput Aided Mol Des Asunto de la revista: BIOLOGIA MOLECULAR / ENGENHARIA BIOMEDICA Año: 2020 Tipo del documento: Article País de afiliación: México Pais de publicación: Países Bajos