Neuroreceptor Activation by Vibration-Assisted Tunneling

Ross Hoehn, David Nichols, Hartmut Neven, Sabre Kais

Research output: Contribution to journalArticle

5 Citations (Scopus)

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.

Original languageEnglish
Article number9990
JournalScientific Reports
Volume5
DOIs
Publication statusPublished - 24 Apr 2015

Fingerprint

Sensory Receptor Cells
G-Protein-Coupled Receptors
Vibration
Drug Design
Lysergic Acid
Physiological Phenomena
Serotonin Receptor Agonists
Computer Simulation
Nervous System
Signal Transduction
Spectrum Analysis
Serotonin
Pharmacology
Electrons
Proteins

ASJC Scopus subject areas

  • General

Cite this

Neuroreceptor Activation by Vibration-Assisted Tunneling. / Hoehn, Ross; Nichols, David; Neven, Hartmut; Kais, Sabre.

In: Scientific Reports, Vol. 5, 9990, 24.04.2015.

Research output: Contribution to journalArticle

@article{e2139f5b963740a29591ca7f8c8e7553,
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.",
author = "Ross Hoehn and David Nichols and Hartmut Neven and Sabre Kais",
year = "2015",
month = "4",
day = "24",
doi = "10.1038/srep09990",
language = "English",
volume = "5",
journal = "Scientific Reports",
issn = "2045-2322",
publisher = "Nature Publishing Group",

}

TY - JOUR

T1 - Neuroreceptor Activation by Vibration-Assisted Tunneling

AU - Hoehn, Ross

AU - Nichols, David

AU - Neven, Hartmut

AU - Kais, Sabre

PY - 2015/4/24

Y1 - 2015/4/24

N2 - 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.

AB - 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.

UR - http://www.scopus.com/inward/record.url?scp=84928548655&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=84928548655&partnerID=8YFLogxK

U2 - 10.1038/srep09990

DO - 10.1038/srep09990

M3 - Article

VL - 5

JO - Scientific Reports

JF - Scientific Reports

SN - 2045-2322

M1 - 9990

ER -