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 identifcation of activity clifs, scafolds hops and other active an inactive molecules with distinct
SAR. Structure-based analysis of activity clifs, scafold hops and other selected active and inactive G9a inhibitors by means
of docking followed by molecular dynamics simulations led to the identifcation 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
