变构调节
化学
变构调节剂
结构-活动关系
突变
G蛋白偶联受体
数量结构-活动关系
药物发现
受体
体内
生物物理学
计算生物学
立体化学
生物化学
体外
基因
生物
突变
生物技术
作者
Corinna Schüß,Oanh Vu,Nigam M. Mishra,Iain R. Tough,Yu Du,Jan Stichel,Helen Cox,C. David Weaver,Jens Meiler,Kyle A. Emmitte,Annette G. Beck‐Sickinger
标识
DOI:10.1021/acs.jmedchem.3c00383
摘要
Positive allosteric modulators targeting the Y4 receptor (Y4R), a G protein-coupled receptor (GPCR) involved in the regulation of satiety, offer great potential in anti-obesity research. In this study, we selected 603 compounds by using quantitative structure–activity relationship (QSAR) models and tested them in high-throughput screening (HTS). Here, the novel positive allosteric modulator (PAM) VU0506013 was identified, which exhibits nanomolar affinity and pronounced selectivity toward the Y4R in engineered cell lines and mouse descending colon mucosa natively expressing the Y4R. Based on this lead structure, we conducted a systematic SAR study in two regions of the scaffold and presented a series of 27 analogues with modifications in the N- and C-terminal heterocycles of the molecule to obtain insight into functionally relevant positions. By mutagenesis and computational docking, we present a potential binding mode of VU0506013 in the transmembrane core of the Y4R. VU0506013 presents a promising scaffold for developing in vivo tools to move toward anti-obesity drug research focused on the Y4R.
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