Centre for Sport, Exercise and Life Sciences, Faculty of Health and Life Sciences, Coventry University, Alison Gingell Building, Coventry CV1 5FB, U.K.
Department of Pharmacology, University of Cambridge, Tennis Court Road, Cambridge CB2 1PD, U.K.
J Chem Inf Model. 2021 Apr 26;61(4):2001-2015. doi: 10.1021/acs.jcim.0c01331. Epub 2021 Mar 29.
Despite being a target for about one-third of approved drugs, G protein-coupled receptors (GPCRs) still represent a tremendous reservoir for therapeutic strategies against diseases. For example, several cardiovascular and central nervous system conditions could benefit from clinical agents that activate the adenosine 1 receptor (AR); however, the pursuit of AR agonists for clinical use is usually impeded by both on- and off-target side effects. One of the possible strategies to overcome this issue is the development of positive allosteric modulators (PAMs) capable of selectively enhancing the effect of a specific receptor subtype and triggering functional selectivity (a phenomenon also referred to as bias). Intriguingly, besides enforcing the effect of agonists upon binding to an allosteric site, most of the AR PAMs display intrinsic partial agonism and orthosteric competition with antagonists. To rationalize this behavior, we simulated the binding of the prototypical PAMs PD81723 and VCP171, the full-agonist NECA, the antagonist 13B, and the bitopic agonist VCP746. We propose that a single PAM can bind several AR sites rather than a unique allosteric pocket, reconciling the structure-activity relationship and the mutagenesis results.
尽管 G 蛋白偶联受体 (GPCR) 是约三分之一已批准药物的靶标，但它们仍然是针对疾病的治疗策略的巨大宝库。例如，几种心血管和中枢神经系统疾病可能受益于激活腺苷 1 受体 (AR) 的临床药物；然而，由于存在靶内和靶外副作用，通常会阻碍 AR 激动剂的临床应用。克服这个问题的一种可能策略是开发能够选择性增强特定受体亚型作用并引发功能选择性的正变构调节剂 (PAM)（也称为偏倚）。有趣的是，除了在结合变构位点时增强激动剂的作用外，大多数 AR PAMs 还表现出内在部分激动作用和与拮抗剂的正构竞争。为了使这种行为合理化，我们模拟了原型 PAMs PD81723 和 VCP171、完全激动剂 NECA、拮抗剂 13B 和双位点激动剂 VCP746 的结合。我们提出，单个 PAM 可以结合多个 AR 位点，而不是一个独特的变构口袋，从而协调结构-活性关系和突变体结果。
