Structural Biochemistry and the Opioid Crisis: Using the Primary Literature to Teach Core Concepts and Underscore the Societal Relevance of Biochemical Research

Abstract

Macromolecular structure, interactions and dynamics are essential underpinnings of an education in biochemistry. Biochemists often convey these core concepts by systematically probing the structure function relationship of archetypal proteins. G‐protein–coupled receptors are the largest class of signaling receptors in the genome and the target of over 30% of marketed drugs. The mu opioid receptor (MOR) is a member of this influential receptor family and constitutes the main opioid target for the management of pain. Insight into opioid action has been facilitated by acquiring structures of the MOR in inactive and agonist‐induced active states. Importantly, these structures enabled the application of structure‐based approaches to drug discovery in a quest to find an ideal opioid that elicits analgesia but fails to trigger the respiratory depression associated with the epidemic of opioid‐induced deaths.To provide an authentic learning experience, a primary literature module that explores the structure function of the MOR, and the ongoing work on developing optimized opioids as well as non‐opioid analgesics was integrated into our undergraduate biochemistry class. Students in the class undertook a deep reading of the primary papers detailing MOR structure and then addressed questions on the mode of ligand engagement and signal transduction in a think‐pair‐share method during class time. In a subsequent class session, teams of students critically assessed findings from published studies on designing ‘biased’ opioids that activate signaling pathways relevant to analgesia, but not those that produce unwanted effects. To complement this focus on the biochemistry of opioid analgesics, primary papers that detail the development of non‐opioid alternatives for the pharmacological treatment of pain were probed. Since humans with loss‐of‐function mutations in the gene that codes for the sodium channel subtype Nav1.7 exhibit complete insensitivity to pain, a literature review session focused on the diverse biochemical approaches being used to develop potent, selective inhibitors of Nav1.7. This literature module succeeded in illuminating the contemporary relevance of structural biochemistry by delving into the molecular interactions relevant to the escalating opioid crisisThis abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.