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arXiv · 1503.07441

Neuroreceptor Activation by Vibration-Assisted Tunneling

Ross D. Hoehn·David Nichols·Hartmut Neven·Sabre Kais
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Abstract

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 hypothesis 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.

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Ross D. Hoehn, David Nichols, Hartmut Neven, Sabre Kais. 2015-03-24. Neuroreceptor Activation by Vibration-Assisted Tunneling. https://doi.org/10.1038/srep09990

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