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.
Cite
@article{arxiv.1503.07441,
title = {Neuroreceptor Activation by Vibration-Assisted Tunneling},
author = {Ross D. Hoehn and David Nichols and Hartmut Neven and Sabre Kais},
journal= {arXiv preprint arXiv:1503.07441},
year = {2015}
}
Comments
Accepted to Scientific Reports; Main text 15 pgs with 4 figs; Sup Materials 10 pgs 7 figs