Mechanistic origin of partial agonism of tetrahydrocannabinol for cannabinoid receptors.
Mechanistic origin of partial agonism of tetrahydrocannabinol for cannabinoid receptors.
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DOI：
10.1016/j.jbc.2022.101764
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发表时间：
2022-04
期刊：
影响因子：
--
通讯作者：
Shukla D
中科院分区：
文献类型：
--
作者：
Dutta S;Selvam B;Das A;Shukla D
大麻素受体1（CB 1）是控制疼痛、肥胖和其他中枢神经系统疾病的治疗相关药物靶点。然而，CB 1的完全激动剂和拮抗剂已被报道在患者中引起严重的副作用。因此，部分激动剂已经成为一种可行的替代方案，因为它们可以减轻过度刺激和副作用。然而，设计部分激动剂的关键瓶颈之一是缺乏对部分激动作用本身的分子机制的理解。在这项研究中，我们研究了大麻素受体部分激动作用起源的两种机制假设，并预测了Δ9-四氢大麻酚（THC）对CB 1表现出的部分激动作用的机制基础。特别是，我们检查是否出现部分激动从THC的能力，结合在激动剂和拮抗剂结合的姿势，或从它的能力，只有部分激活受体。我们使用了广泛的分子动力学模拟和马尔可夫状态建模，以捕捉在CB 1受体的拮抗剂和激动剂结合姿势的THC结合。此外，我们预测THC在激动剂结合姿势中的结合导致拨动开关残基的旋转，并导致细胞内跨膜螺旋6（TM 6）的部分向外移动。我们的模拟还表明，THC的烷基侧链起着至关重要的作用，在确定部分激动剂通过稳定的激动剂和拮抗剂样的口袋内的姿势配体。两者合计，这项研究提供了重要的见解THC的部分激动的机制起源。
Cannabinoid receptor 1 (CB1) is a therapeutically relevant drug target for controlling pain, obesity, and other central nervous system disorders. However, full agonists and antagonists of CB1 have been reported to cause serious side effects in patients. Therefore, partial agonists have emerged as a viable alternative as they can mitigate overstimulation and side effects. One of the key bottlenecks in the design of partial agonists, however, is the lack of understanding of the molecular mechanism of partial agonism itself. In this study, we examine two mechanistic hypotheses for the origin of partial agonism in cannabinoid receptors and predict the mechanistic basis of partial agonism exhibited by Δ9-Tetrahydrocannabinol (THC) against CB1. In particular, we inspect whether partial agonism emerges from the ability of THC to bind in both agonist and antagonist-binding poses or from its ability to only partially activate the receptor. We used extensive molecular dynamics simulations and Markov state modeling to capture the THC binding in both antagonist and agonist-binding poses in the CB1 receptor. Furthermore, we predict that binding of THC in the agonist-binding pose leads to rotation of toggle switch residues and causes partial outward movement of intracellular transmembrane helix 6 (TM6). Our simulations also suggest that the alkyl side chain of THC plays a crucial role in determining partial agonism by stabilizing the ligand in the agonist and antagonist-like poses within the pocket. Taken together, this study provides important insights into the mechanistic origin of the partial agonism of THC.
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影响因子：
5.6
作者：
Ibsen, Mikkel Soes;Finlay, David B.;Grimsey, Natasha Lillia
通讯作者：
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影响因子：
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发表时间：
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Perspectives in medicinal chemistry
影响因子：
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影响因子：
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影响因子：
2.9
作者：
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