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.

中文翻译：

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理解 G9a 抑制剂的活性：一种活性景观和分子建模方法。

在这项工作中，我们使用组合的活性景观、分子对接和分子动力学方法分析了表观遗传抑制剂（赖氨酸模拟物）对赖氨酸甲基转移酶（G9a 或 EHMT2）的构效关系（SAR）。该研究基于一组 251 种具有实验活性的 G9a 抑制剂。活动景观分析迅速导致对活动悬崖、脚手架啤酒花和其他具有明显 SAR 的活性和非活性分子的识别。通过对接和分子动力学模拟，对活性悬崖、支架啤酒花和其他选定的活性和非活性 G9a 抑制剂进行基于结构的分析，从而识别出与参与抗 G9a 活性的关键残基的相互作用，例如与 ASP 1083、LEU 1086 、ASP 1088、TYR 1154 和 PHE 1158。