Hoehn Ross D, Nichols David, Neven Hartmut, Kais Sabre
Department of Chemistry, Purdue University, West Lafayette, IN 47907, USA.
Department of Medicinal Chemistry and Molecular Pharmacology, Purdue University, West Lafayette, IN 47907, USA.
Sci Rep. 2015 Apr 24;5:9990. doi: 10.1038/srep09990.
G protein-coupled receptors (GPCRs) constitute a large family of receptor proteins that sense molecular signals on the exterior of a cell and activate signal transduction pathways within the cell. Modeling how an agonist activates such a receptor is fundamental for an understanding of a wide variety of physiological processes and it is of tremendous value for pharmacology and drug design. Inelastic electron tunneling spectroscopy (IETS) has been proposed as a model for the mechanism by which olfactory GPCRs are activated by a bound agonist. We apply this hyothesis to GPCRs within the mammalian nervous system using quantum chemical modeling. We found that non-endogenous agonists of the serotonin receptor share a particular IET spectral aspect both amongst each other and with the serotonin molecule: a peak whose intensity scales with the known agonist potencies. We propose an experiential validation of this model by utilizing lysergic acid dimethylamide (DAM-57), an ergot derivative, and its deuterated isotopologues; we also provide theoretical predictions for comparison to experiment. If validated our theory may provide new avenues for guided drug design and elevate methods of in silico potency/activity prediction.
G蛋白偶联受体（GPCRs）构成了一个庞大的受体蛋白家族，它们能够感知细胞外部的分子信号并激活细胞内的信号转导途径。模拟激动剂如何激活这类受体对于理解多种生理过程至关重要，并且对药理学和药物设计具有巨大价值。非弹性电子隧穿光谱（IETS）已被提议作为嗅觉GPCRs被结合的激动剂激活的机制模型。我们使用量子化学建模将这一假设应用于哺乳动物神经系统中的GPCRs。我们发现血清素受体的非内源性激动剂彼此之间以及与血清素分子都共享一个特定的IET光谱特征：一个强度与已知激动剂效力成正比的峰。我们提议通过利用麦角衍生物麦角酸二乙酰胺（DAM - 57）及其氘代同位素类似物对该模型进行经验验证；我们还提供理论预测以供与实验进行比较。如果得到验证，我们的理论可能为定向药物设计提供新途径，并提升计算机模拟效力/活性预测的方法。
