Identification and development of a small molecule probe for HNMT

小分子甲基转移酶（SMMTases）催化甲基从s -腺苷蛋氨酸（SAM）转移到小代谢物的N-、O-或C-原子上。smmtase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，在关键的信号通路中起作用。其他SMMTases在临床中发挥着重要作用。一些SMMTase缺陷被GARD认定为罕见病。尽管smmtase在调节关键生物过程中具有重要作用，但作为治疗或探针开发的候选物，smmtase在很大程度上被忽视了。SMMTases是目标类分析的理想选择。

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.