Medicinal Chemistry Laboratory, University of Veracruz, Agustín de Iturbide Esq. Carmen Serdan, 91700 Veracruz, Mexico.
Department of Pharmacy, School of Chemistry, National Autonomous University of Mexico, 04510 Mexico City, Mexico.
Molecules. 2018 Dec 11;23(12):3282. doi: 10.3390/molecules23123282.
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 methyltransferase (G9a) and DNA methyltranferase 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 differences. 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.
在这项工作中，我们讨论了从活性景观、对接和分子动力学角度对双重表观遗传靶点抑制剂（组蛋白甲基转移酶（G9a）和 DNA 甲基转移酶 1（DNMT1））的结构-活性关系的深入了解。该研究基于 50 种已发表化合物的新型数据集，这些化合物对两种靶点均具有报道的实验活性。活性景观分析揭示了活性悬崖的存在，例如，具有高结构相似性但活性差异较大的化合物对。通过分子对接和动力学模拟进一步从分子水平上对活性悬崖进行了合理化，这些模拟导致了与双重活性或与表观遗传靶点选择性相关的关键残基相互作用的鉴定。
