Towards the understanding of the activity of G9a inhibitors: an activity landscape and molecular modeling approach

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 wi...

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Bibliographic Details
Published in:Journal of computer-aided molecular design 2020-06, Vol.34 (6), p.659-669
Main Authors: López-López, Edgar, Rabal, Obdulia, Oyarzabal, Julen, Medina-Franco, José L.
Format: Article
Language:English
Subjects:
Animal Anatomy
Chemistry
Chemistry and Materials Science
Cliffs
Computer Applications in Chemistry
Computer simulation
Histology
Inhibitors
Lysine
Molecular docking
Molecular dynamics
Molecular structure
Morphology
Physical Chemistry
Scaffolds
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Summary: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.
ISSN:0920-654X
1573-4951
DOI:10.1007/s10822-020-00298-x