Identification and development of a small molecule probe for HNMT

小分子甲基转移酶（SMMT酶）催化甲基从S-腺苷甲硫氨酸（SAM）转移到小代谢物的N-、0-或C-原子。SMMT酶与保守的SAM结合基序共享Rossman样折叠，但作用于多种底物。许多SMMTase底物，如去甲肾上腺素和组胺，在关键信号通路中起作用。其他SMMT酶在临床上起着油酸甘油酯的作用。几种SMMTase缺乏症被GARD认为是罕见疾病。尽管SMMT酶在调节关键生物过程中具有重要性，但其作为治疗或探针开发的候选者在很大程度上被忽视。SMMT酶是目标类分析的理想候选者。 在本报告所述期间，合作团队针对几种化合物集合筛选了小分子甲基转移酶HNMT（组胺N-甲基转移酶）。药物化学优化正在进行中，以提高已确定的命中系列的效力和药物样性质，X射线共结晶工作正在进行中，以帮助基于结构的药物设计。

Small molecule methyltransferases (SMMTases) catalyze the transfer of a methyl group from S-adenosylmethionine (SAM) to the N-, O-, or C- atom of a small metabolite. SMMTases share a Rossman-like fold with a conserved SAM-binding motif, but act on a diverse array of substrates. Many SMMTase substrates, such as norepinephrine and histamine, act in key signaling pathways. Others SMMTases play a olein in the clinic. Several SMMTase deficiencies are recognized by GARD as rare diseases. Despite their importance in regulating key biological processes, SMMTases have gone largely ignored as candidates for therapeutic or probe development. SMMTases are ideal candidates for target class profiling. During this reporting period, the collaborative team screened the small molecule methyl transferase HNMT (histamine N-methyl transferase) against several compound collections. Medicinal chemistry optimization is ongoing to improve potency and drug-like properties of identified hit series, and X-ray co-crystallization work is underway to aid in structure-based drug design.