新型多巴胺D_3受体抑制剂的发现

Discovery of a Novel Dopamine D_3 Receptor Inhibitor

根据最新解析的多巴胺D3受体的晶体结构进行活性位点分析,建立了基于受体的药效团模型,并对Asinex Gold Collection数据库进行筛选,选择7个化合物进行生物活性测试,得到了高活性新型多巴胺受体抑制剂(04932482),它对多巴胺D3受体抑制率达85.45%,其Ki值为(806.75±34.58)nmol/L.进一步对活性化合物进行结构分析,研究了其与受体相互作用的模式,并以此为指导提出以04932482为先导化合物进行结构改造的方向.

Dopamine D3 receptor regulates the synthesis and release of dopamine in brain.It is implicated in many neurological processes,including motivation,pleasure,cognition,memory,learning,and fine motor control.It is involved in the pathology of psychotic diseases,such as schizophrenia,Parkinson＇s disease and drug addiction.It is of great significance to discover novel D3 inhibitors through pharmacophore-based virtual screening for the development of anti-psychotic drugs.In this study,we employed the latest discovered high-resolution crystal structure of human D3 receptor to conduct active-site-analysis,build the receptor-based pharmacophore model and screen the Asinex GOLD Collection database.7 hits were purchased and tested by pharmacological experiments.A novel inhibitor 04932482 with a high activity against D3 receptor was obtained[Ki=（806.75±34.58） nmol/L].The structure analysis was conducted and the ligand-receptor interaction was further investigated by docking to guide the structure modification and optimization of compound 04932482.