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Insights From Molecular Dynamics Simulations of a Number of G-Protein Coupled Receptor Targets for the Treatment of Pain and Opioid Use Disorders.

ABSTRACT: Effective treatments for pain management remain elusive due to the dangerous side-effects of current gold-standard opioid analgesics, including the respiratory depression that has led to skyrocketing death rates from opioid overdoses over the past decade. In an attempt to address the horrific opioid crisis worldwide, the National Institute on Drug Abuse has recently proposed boosting research on specific pharmacological mechanisms mediated by a number of G protein-coupled receptors (GPCRs). This research is expected to expedite the discovery of medications for opioid overdose and opioid use disorders, leading toward a safer and more effective treatment of pain. Here, we review mechanistic insights from recent all-atom molecular dynamics simulations of a specific subset of GPCRs for which high-resolution experimental structures are available, including opioid, cannabinoid, orexin, metabotropic glutamate, and dopamine receptor subtypes.

SUBMITTER: Ribeiro JML

PROVIDER: S-EPMC6716474 | biostudies-literature | 2019

REPOSITORIES: biostudies-literature

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Insights From Molecular Dynamics Simulations of a Number of G-Protein Coupled Receptor Targets for the Treatment of Pain and Opioid Use Disorders.

Ribeiro João Marcelo Lamim JML Filizola Marta M

Frontiers in molecular neuroscience 20190823

Effective treatments for pain management remain elusive due to the dangerous side-effects of current gold-standard opioid analgesics, including the respiratory depression that has led to skyrocketing death rates from opioid overdoses over the past decade. In an attempt to address the horrific opioid crisis worldwide, the National Institute on Drug Abuse has recently proposed boosting research on specific pharmacological mechanisms mediated by a number of G protein-coupled receptors (GPCRs). This ...[more]

PMID: 31507375

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Project description:Epitope recognition by major histocompatibility complex II (MHC-II) is essential for the activation of immunological responses to infectious diseases. Several studies have demonstrated that this molecular event takes place in the MHC-II peptide-binding groove constituted by the α and β light chains of the heterodimer. This MHC-II peptide-binding groove has several pockets (P1-P11) involved in peptide recognition and complex stabilization that have been probed through crystallographic experiments and in silico calculations. However, most of these theoretical calculations have been performed without taking into consideration the heavy chains, which could generate misleading information about conformational mobility both in water and in the membrane environment. Therefore, in absence of structural information about the difference in the conformational changes between the peptide-free and peptide-bound states (pMHC-II) when the system is soluble in an aqueous environment or non-covalently bound to a cell membrane, as the physiological environment for MHC-II is. In this study, we explored the mechanistic basis of these MHC-II components using molecular dynamics (MD) simulations in which MHC-II was previously co-crystallized with a small epitope (P7) or coupled by docking procedures to a large (P22) epitope. These MD simulations were performed at 310 K over 100 ns for the water-soluble (MHC-IIw, MHC-II-P(7w), and MHC-II-P(22w)) and 150 ns for the membrane-bound species (MHC-IIm, MHC-II-P(7m), and MHC-II-P(22m)). Our results reveal that despite the different epitope sizes and MD simulation environments, both peptides are stabilized primarily by residues lining P1, P4, and P6-7, and similar noncovalent intermolecular energies were observed for the soluble and membrane-bound complexes. However, there were remarkably differences in the conformational mobility and intramolecular energies upon complex formation, causing some differences with respect to how the two peptides are stabilized in the peptide-binding groove.

Dataset Information

Insights From Molecular Dynamics Simulations of a Number of G-Protein Coupled Receptor Targets for the Treatment of Pain and Opioid Use Disorders.

Publications

Insights From Molecular Dynamics Simulations of a Number of G-Protein Coupled Receptor Targets for the Treatment of Pain and Opioid Use Disorders.

Similar Datasets

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