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While current opioids on the market are useful for Pain Management, opioid abuse has become a widespread problem in the United States and deaths from opioid overdose are numerous and increasing (1). According to the Centers for Disease Control and Prevention (CDC), more than 47,000 Americans died of opioid overdoses in 2017. The analgesic and addictive effect of opioids are exerted mainly though μOR (2-9). Recently, experimental analgesics with reduced side effects such as IBNtxA (10) and PZM21(11) have been developed. In animal studies, these drugs lack side effects such as respiratory suppression, significant constipation, physical dependence and behavioral reinforcement. IBNtxA seems to achieve this by selectively binding to truncated splice variants of μOR (10). PZM21 binds to the full length isoform but unlike morphine or heroin it activates only the G protein-dependent signal transduction cascade and not the G protein-independent pathway (11), which is referred to as functional selectivity. In order to design drugs like IBNtxA and PZM21, it is critical to better understand how drug binding causes the conformational change of μOR from the inactive to active state. Fortunately, X-ray crystal structures of murine μOR exist for the both states (12, 13). Binding modes of opioid drugs to human μOR will be computationally predicted, and the predicted binding modes will be tested using site-directed mutagenesis and covalent modification of μOR together with the two-electrode voltage clamp (TEVC) technique. The activation mechanism of μOR will then be investigated using molecular dynamics (MD) simulation.
Opioid Project Background Information References
Opioid Project Background Information References
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