Molecular and Dynamic Insights into the Function of GPCRs Involved in Drug Abuse

美国因吸毒过量死亡人数创历史新高，远远超过枪支死亡人数 或者是车祸。其中60%的死亡是由非法药物(例如海洛因)或合法药物造成的 处方类阿片(如奥施康定和博可赛)。这不仅引起了联邦政府的注意 政府提出具体要求，通过加强毒品跟踪、执法和公众宣传来解决这一问题 意识，但医生也改变了他们治疗疼痛的方式，变得更加犹豫是否开处方 阿片类药物，因为围绕其滥用的争议。然而，对疼痛的有效治疗 对于超过1.1亿患有慢性疼痛的美国成年人，仍然缺乏管理，以及完整的 要解决这个问题，很可能需要在分子水平上了解这些药物是如何发挥作用的 以确定如何微调阿片类药物信号朝向所需的治疗途径，而不是 那些调解不利影响的人。这些信息对于最终设计强大的化学工具是必不可少的 可能会发展成改进的疗法。 越来越多的证据表明阿片类变构调节剂和G蛋白偏向 阿片类激动剂可以起到改善止痛药的作用，同时减少副作用，这是这项工作的总体目标 本申请中描述的是获得关于替代(变构)结合位点和/或 阿片受体配体特异性(偏向)构象，包括药物-受体结合动力学的细节， 作为新的、令人兴奋的途径，最终发现改进的疗法。为此，我们将聘请一名 计算驱动的阿片受体独特机制研究假说生成方法 将由独立资助的调查人员反复测试的功能。这些研究预计将 通过帮助我们确定阿片类变构调节的价值，显著影响生物医学研究， 药物发现中的偏向激动论和结合动力学。

Deaths from drug overdoses have hit record numbers in the US, far exceeding the number of deaths from guns or car accidents. Sixty percent of these deaths are caused by either illegal drugs (e.g., heroin) or legal prescription opioids (e.g., Oxycontin and Percocet). Not only has this drawn the attention of the federal government with specific requests to address the issue by increasing drug tracking, enforcement, and public awareness, but also doctors have changed the way they treat pain, becoming more hesitant to prescribe opioids because of the controversy surrounding their abuse. However, effective treatments for pain management are still lacking for the over 110 million American adults suffering from chronic pain, and a full resolution of the problem will most likely require a molecular level understanding of how these drugs work so as to determine how to fine-tune opioid signaling towards the desired therapeutic pathways and away from those mediating adverse effects. This information is essential to eventually design powerful chemical tools that may be developed into improved therapeutics. Building upon the growing body of evidence suggesting that opioid allosteric modulators and G protein-biased opioid agonists may act as improved painkillers with reduced side effects, the overall goal of the work described in this application is to obtain atomistic information about alternative (allosteric) binding sites and/or ligand-specific (biased) conformations of opioid receptors, including details of drug-receptor binding kinetics, for use as new, exciting avenues to eventually discover improved therapeutics. To this end, we will employ a computation-driven approach for hypothesis generation of unique mechanistic insights into opioid receptor function that will be tested iteratively by independently funded investigators. These studies are expected to significantly impact biomedical research by helping us establish the value of opioid allosteric modulation, biased agonism, and binding kinetics in drug discovery.