Department of Pharmaceutical Sciences, Computational Chemical Genomics Screening Center, and Pharmacometrics & System Pharmacology PharmacoAnalytics, School of Pharmacy; National Center of Excellence for Computational Drug Abuse Research; Drug Discovery Institute; Departments of Computational Biology and Structural Biology, School of Medicine, University of Pittsburgh, Pittsburgh, Pennsylvania 15261, United States.
Department of Pharmaceutical Sciences, Computational Chemical Genomics Screening Center, and Pharmacometrics & System Pharmacology PharmacoAnalytics, School of Pharmacy; National Center of Excellence for Computational Drug Abuse Research; Drug Discovery Institute; Departments of Computational Biology and Structural Biology, School of Medicine, University of Pittsburgh, Pittsburgh, Pennsylvania 15261, United States.
Drug Discov Today. 2023 Jul;28(7):103615. doi: 10.1016/j.drudis.2023.103615. Epub 2023 May 11.
Although drugs targeting the orthosteric binding site of cannabinoid receptors (CBRs) have several therapeutic effects on human physiological and pathological conditions, they can also cause serious adverse effects. Only a few orthosteric ligands have successfully passed clinical trials. Recently, allosteric modulation has become a novel option for drug discovery, with fewer adverse effects and the potential to avoid drug overdose. In this review, we highlight novel findings related to the drug discovery of allosteric modulators (AMs) targeting CBRs. We summarize newly synthesized AMs and the reported/predicted allosteric binding sites. We also discuss the structural determinants of the AMs binding as well as the molecular mechanism of CBR allostery.
虽然靶向大麻素受体（CBRs）的变构结合位点的药物对人类生理和病理状况有多种治疗作用，但也会引起严重的不良反应。只有少数变构配体成功通过了临床试验。最近，变构调节已成为药物发现的一种新选择，其不良反应较少，且有可能避免药物过量。在这篇综述中，我们重点介绍了与靶向 CBR 的变构调节剂（AMs）的药物发现相关的新发现。我们总结了新合成的 AMs 和报告/预测的变构结合位点。我们还讨论了 AMs 结合的结构决定因素以及 CBR 变构的分子机制。
