G protein-coupled receptors (GPCRs) orchestrate many physiological functions and are a crucial target in drug discovery. Adhesion GPCRs (aGPCRs), the second largest family within this superfamily, are promising yet underexplored targets for treating various diseases, including obesity, psychiatric disorders, and cancer. However, the receptors’ unique and complex structure and miscellaneous interactions complicate comprehensive pharmacological studies. Despite recent progress in determining structures and elucidation of the activation mechanism, the function of many receptors remains to be determined.This review consolidates current knowledge on aGPCR ligands, focusing on small molecule orthosteric ligands and allosteric modulators identified for the ADGRGs subfamily (subfamily VIII), (GPR56/ADGRG1, GPR64/ADGRG2, GPR97/ADGRG3, GPR114/ADGRG5, GPR126/ADGRG6, and GPR128/ADGRG7). We discuss challenges in hit identification, target validation, and drug discovery, highlighting molecular compositions and recent structural breakthroughs. ADGRG ligands can offer new insights into aGPCR modulation and have significant potential for novel therapeutic interventions targeting various diseases.

中文翻译：

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靶向粘附 G 蛋白偶联受体。现状和未来展望


G 蛋白偶联受体 （GPCR） 协调许多生理功能，是药物发现的关键靶标。粘附 GPCR （aGPCR） 是该超家族中的第二大家族，是治疗各种疾病（包括肥胖、精神疾病和癌症）的有前途但未被充分开发的靶点。然而，受体独特而复杂的结构和杂项相互作用使综合药理学研究复杂化。尽管最近在确定结构和阐明激活机制方面取得了进展，但许多受体的功能仍有待确定。本文巩固了当前关于 aGPCR 配体的知识，重点介绍了 ADGRGs 亚家族 （亚家族 VIII） （GPR56/ADGRG1、GPR64/ADGRG2、GPR97/ADGRG3、GPR114/ADGRG5、GPR126/ADGRG6 和 GPR128/ADGRG7）鉴定的小分子正构配体和变构调节剂。我们讨论了苗头化合物识别、靶标验证和药物发现方面的挑战，重点介绍了分子组成和最近的结构突破。ADGRG 配体可以为 aGPCR 调节提供新的见解，并为针对各种疾病的新型治疗干预具有巨大潜力。