Abstract
Opioid receptors that belong to class A G protein-coupled receptors (GPCRs) are vital in pain control. In the past few years, published high-resolution crystal structures of opioid receptor laid a solid basis for both experimental and computational studies. Computer-aided drug design (CADD) has been established as a powerful tool for discovering novel lead compounds and for understanding activation mechanism of target receptors. Herein, we reviewed the computational-guided studies on opioid receptors for the discovery of new analgesics, the structural basis of receptor subtype selectivity, agonist interaction mechanism, and biased signaling mechanism.
Highlights
G protein-coupled receptors (GPCRs), known as hepta-helical receptors, are characterized as α-helix domains which span the cell membrane seven times (King et al, 2003)
After studying the interaction between μ receptor and other targets, researchers raised the concept of bifunctional μ receptor agonists. They found that the δ receptor agonists can enhance the analgesic effect of the μ receptor agonists, while the δ receptor antagonists can significantly improve or even completely block the side effects of addiction, tolerance, and respiratory inhibition caused by the μ receptor agonists (Abdelhamid et al, 1991; Porreca et al, 1992)
Additional study of opioid receptor function has demonstrated that G protein conjugation pathway of μ opioid receptor mainly induces analgesic effect, while the β-arrestin pathway can lead to side effects such as respiratory depression, nausea, and constipation (Violin et al, 2014)
Summary
G protein-coupled receptors (GPCRs), known as hepta-helical receptors, are characterized as α-helix domains which span the cell membrane seven times (King et al, 2003). After studying the interaction between μ receptor and other targets, researchers raised the concept of bifunctional μ receptor agonists They found that the δ receptor agonists can enhance the analgesic effect of the μ receptor agonists, while the δ receptor antagonists can significantly improve or even completely block the side effects of addiction, tolerance, and respiratory inhibition caused by the μ receptor agonists (Abdelhamid et al, 1991; Porreca et al, 1992). Additional study of opioid receptor function has demonstrated that G protein conjugation pathway of μ opioid receptor mainly induces analgesic effect, while the β-arrestin pathway can lead to side effects such as respiratory depression, nausea, and constipation (Violin et al, 2014) These new concepts need to be tested with extensive follow-up studies, and computational study is an appropriate and efficient test. We will focus on the applications of computational approaches in these topics: (1) discovering opioid analgesics; (2) the molecular mechanisms of opioid subtype selectivity; (3) the mechanism of the opioid receptor activation, and the G proteinbiased activation
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