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Fragment-based discovery of subtype-selective adenosine receptor ligands from homology models

机译:基于同源模型的亚型选择性腺苷受体配体的基于片段的发现

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摘要

Fragment-based lead discovery (FBLD) holds great promise for drug discovery, but applications to G protein-coupled receptors (GPCRs) have been limited by a lack of sensitive screening techniques and scarce structural information. If virtual screening against homology models of GPCRs could be used to identify fragment ligands, FBLD could be extended to numerous important drug targets and contribute to efficient lead generation. Access to models of multiple receptors may further enable the discovery of fragments that bind specifically to the desired target. To investigate these questions, we used molecular docking to screen >500 000 fragments against homology models of the A3 and A1 adenosine receptors (ARs) with the goal to discover A3AR-selective ligands. Twenty-one fragments with predicted A3AR-specific binding were evaluated in live-cell fluorescence-based assays; of eight verified ligands, six displayed A3/A1 selectivity, and three of these had high affinities ranging from 0.1 to 1.3 μM. Subsequently, structure-guided fragment-to-lead optimization led to the identification of a >100-fold-selective antagonist with nanomolar affinity from commercial libraries. These results highlight that molecular docking screening can guide fragment-based discovery of selective ligands even if the structures of both the target and antitarget receptors are unknown. The same approach can be readily extended to a large number of pharmaceutically important targets.
机译:基于片段的先导发现(FBLD)在药物发现方面具有广阔的前景,但是由于缺乏灵敏的筛选技术和稀缺的结构信息,G蛋白偶联受体(GPCR)的应用受到了限制。如果可以使用针对GPCR同源性模型的虚拟筛选来鉴定片段配体,则FBLD可以扩展到许多重要的药物靶标,并有助于有效地产生潜在客户。访问多种受体的模型可以进一步使得发现特异性结合所需靶标的片段成为可能。为了研究这些问题,我们使用分子对接技术针对A3和A1腺苷受体(ARs)的同源性模型筛选了超过500 000个片段,目的是发现A3AR选择性配体。在基于活细胞荧光的测定中评估了21个具有预测的A3AR特异性结合的片段;在8个已验证的配体中,有6个显示出A3 / A1选择性,其中3个具有0.1至1.3μM的高亲和力。随后,结构引导的片段至前导最优化导致从商业文库中鉴定出具有纳摩尔摩尔亲和力的> 100倍选择性拮抗剂。这些结果表明,即使靶标和抗靶标受体的结构都未知,分子对接筛选也可以指导基于片段的选择性配体的发现。相同的方法可以很容易地扩展到许多药学上重要的靶标。

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