Neuroreceptor Activation by Vibration-Assisted Tunneling, 2014

Topics: fascia, g-protein,, pharmacology, GPCRs, silicopotency

Authors: Ross D. Hoehn, David Nichols, Hartmut Neven and Sabre Kais


G protein-coupled receptors (GPCRs) constitute a large family of receptor proteinsthat sense molecular signals on the exterior of a cell and activate signaltransduction pathways within the cell. Modeling how an agonist activates such areceptor is fundamental for an understanding of a wide variety of physiologicalprocesses and it is of tremendous value for pharmacology and drug design. Inelasticelectron tunneling spectroscopy (IETS) has been proposed as a model for themechanism by which olfactory GPCRs are activated by a bound agonist. We apply thishyothesis to GPCRs within the mammalian nervous system using quantum chemicalmodeling. We found that non-endogenous agonists of the serotonin receptor share aparticular IET spectral aspect both amongst each other and with the serotoninmolecule: a peak whose intensity scales with the known agonist potencies. We proposean experiential validation of this model by utilizing lysergic acid dimethylamide(DAM-57), an ergot derivative and its deuterated isotopologues; we also providetheoretical predictions for comparison to experiment. If validated our theory mayprovide new avenues for guided drug design and elevate methods of in silicopotency/activity prediction.

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