Structural probing of off-target G protein-coupled receptor activities within a series of adenosine/adenine congeners.
Structural probing of off-target G protein-coupled receptor activities within a series of adenosine/adenine congeners.
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DOI：
10.1371/journal.pone.0097858
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发表时间：
2014
期刊：
影响因子：
3.7
通讯作者：
Jacobson KA
中科院分区：
文献类型：
--
作者：
Paoletta S;Tosh DK;Salvemini D;Jacobson KA
我们研究了核苷衍生物在微摩尔范围内（主要是在G蛋白偶联受体（GPCRs）上）的脱靶受体相互作用模式，这些核苷衍生物是针对与腺苷受体（ARs）的纳摩尔相互作用而高度设计的。由于使用AR配体治疗中枢神经系统疾病具有相当大的兴趣，我们使用精神活性药物筛选计划（PDSP）来检测这些腺苷/腺嘌呤同系物在41种不同受体、通道和一种转运体上的混杂性。对刚性化的、在N6、C2和5′位置三取代的核苷进行逐步截短，揭示了主要与生物胺受体（如肾上腺素能受体和5 - 羟色胺能受体）的意外相互作用，亲和力高达61纳摩尔。在新位点上一致的构效关系（SAR）组的揭示表明受体家族在分子识别方面具有相似性。对受影响的GPCRs进行的广泛分子建模表明配体的结合模式支持了单个受体上的SAR模式。在某些情况下，配体对接模式与AR结合非常相似，而在其他情况下，配体呈现不同的取向。根据哪些取代基基团可被接受，对不同GPCRs的识别模式进行了聚类，并根据与受体结合位点的互补性进行了解释。因此，对于这组亚结构的类似物，可以预测一些可能的脱靶相互作用（这是药物副作用的一个关注点），有助于设计额外的结构类似物，以消除或增强某些脱靶活性。此外，对于其他GPCRs的不相关结构家族也可以进行类似的分析。
We studied patterns of off-target receptor interactions, mostly at G protein-coupled receptors (GPCRs) in the µM range, of nucleoside derivatives that are highly engineered for nM interaction with adenosine receptors (ARs). Because of the considerable interest of using AR ligands for treating diseases of the CNS, we used the Psychoactive Drug Screening Program (PDSP) for probing promiscuity of these adenosine/adenine congeners at 41 diverse receptors, channels and a transporter. The step-wise truncation of rigidified, trisubstituted (at N6, C2, and 5′ positions) nucleosides revealed unanticipated interactions mainly with biogenic amine receptors, such as adrenergic receptors and serotonergic receptors, with affinities as high as 61 nM. The unmasking of consistent sets of structure activity relationship (SAR) at novel sites suggested similarities between receptor families in molecular recognition. Extensive molecular modeling of the GPCRs affected suggested binding modes of the ligands that supported the patterns of SAR at individual receptors. In some cases, the ligand docking mode closely resembled AR binding and in other cases the ligand assumed different orientations. The recognition patterns for different GPCRs were clustered according to which substituent groups were tolerated and explained in light of the complementarity with the receptor binding site. Thus, some likely off-target interactions, a concern for secondary drug effects, can be predicted for analogues of this set of substructures, aiding the design of additional structural analogues that either eliminate or accentuate certain off-target activities. Moreover, similar analyses could be performed for unrelated structural families for other GPCRs.
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