title: Neuroreceptor activation by vibration-assisted tunneling.
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 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.
authors.affiliation: Department of Chemistry, Purdue University, West Lafayette, IN 47907, USA.
authors.forename: Ross D
authors.initials: RD
authors.lastname: Hoehn
authors.affiliation: Department of Medicinal Chemistry and Molecular Pharmacology, Purdue University, West Lafayette, IN 47907, USA.
authors.forename: David
authors.initials: D
authors.lastname: Nichols
authors.affiliation: Google, Venice, CA 90291, USA.
authors.forename: Hartmut
authors.initials: H
authors.lastname: Neven
authors.affiliation: 1] Department of Chemistry, Purdue University, West Lafayette, IN 47907, USA [2] Department of Physics, Purdue University, West Lafayette, IN 47907, USA [3] Department of Physics, Purdue University, West Lafayette, IN 47907, USA [4] Qatar Environment and Energy Research Institute, Qatar Foundation, Doha, Qatar.
authors.forename: Sabre
authors.initials: S
authors.lastname: Kais
mesh_terms: D002460:Cell Line; D004317:Doxorubicin / Q000737:chemistry / Q000494:pharmacology; D015195:Drug Design; D004583:Electrons; D006801:Humans; D008238:Lysergic Acid Diethylamide / Q000494:pharmacology; D008956:Models, Chemical; D011789:Quantum Theory; D011985:Receptors, Serotonin / Q000737:chemistry / Q000378:metabolism*; D017366:Serotonin Receptor Agonists / Q000494:pharmacology; D015398:Signal Transduction / Q000187:drug effects
chemical_list: D011985:Receptors, Serotonin; D017366:Serotonin Receptor Agonists; D004317:Doxorubicin; D008238:Lysergic Acid Diethylamide