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.
Highlights
Pain is a vital, albeit unpleasant, physiological response to tissue damage, but it can become a disease if it strikes in the absence of tissue injury, or continues long after appropriate tissue healing (Ringkamp et al, 2018)
With an average of 130 Americans dying every day (Centers for Disease Control and Prevention [CDC], 2017), new scientific solutions are desperately needed to effectively manage pain while preventing or treating overdose and opioid use disorder (OUD) manifestations. This recognition recently led the leadership of the National Institutes of Health (NIH) and the National Institutes on Drug Abuse (NIDA) to launch initiatives aimed at accelerating the pace of scientific inquiry that is necessary to Molecular dynamics (MD) Simulations of G protein-coupled receptors (GPCRs) Targets for Pain address the opioid crisis
While we refer the reader elsewhere for an overview of strengths and limitations of MD simulations in their application to GPCRs (e.g., Ribeiro and Filizola, 2019), we review here atomically detailed mechanistic insights from MD simulations of high-resolution experimental structures of a number of GPCR subtypes whose study might lead to faster development of medications for the treatment of pain or OUDs
Summary
Albeit unpleasant, physiological response to tissue damage, but it can become a disease if it strikes in the absence of tissue injury, or continues long after appropriate tissue healing (Ringkamp et al, 2018). To obtain a more thorough investigation of the molecular details of ligand-induced MOP receptor activation, we recently built a Markov state model (MSM) using over 400 μs of MD simulations of the MOP receptor embedded in a POPC/cholesterol membrane mimetic environment with either morphine or TRV-130 bound at the orthosteric binding site (Kapoor et al, 2017).
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