Cannabidiol binding and negative allosteric modulation at the cannabinoid type 1 receptor in the presence of delta-9-tetrahydrocannabinol: An In Silico study
Cannabidiol binding and negative allosteric modulation at the cannabinoid type 1 receptor in the presence of delta-9-tetrahydrocannabinol: An In Silico study
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DOI：
10.1371/journal.pone.0220025
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发表时间：
2019-07-23
期刊：
影响因子：
3.7
通讯作者：
Pessoa-Mahana, C. David
中科院分区：
文献类型：
--
作者：
Chung, Hery;Fierro, Angelica;Pessoa-Mahana, C. David
最近的证据在讨论中提出了大麻二酚可以作为大麻素1型受体的负变构调节剂的可能性。在这里，我们使用计算方法来研究大麻二酚对大麻素受体1型中δ-9-四氢大麻酚的影响以及直接受体阻断的可能性所产生的调制。我们提出了一个假定的变构结合位点，位于受体的N-末端区域，部分重叠的正构结合位点。分子动力学模拟揭示了一个协调的运动，涉及向外旋转的螺旋1和2和随后的扩张的orthosteric结合位点大麻二酚结合。最后，细胞质区域的变化和高螺旋8流动性与受损的受体内化有关。总之，这些结果为大麻二酚如何直接调节δ-9-四氢大麻酚对大麻素受体1型的影响提供了可能的解释。
Recent evidence has raised in discussion the possibility that cannabidiol can act as a negative allosteric modulator of the cannabinoid type 1 receptor. Here we have used computational methods to study the modulation exerted by cannabidiol on the effects of delta-9-tetrahydrocannabinol in the cannabinoid receptor type 1 and the possibility of direct receptor blockade. We propose a putative allosteric binding site that is located in the N-terminal region of receptor, partially overlapping the orthosteric binding site. Molecular dynamics simulations reveled a coordinated movement involving the outward rotation of helixes 1 and 2 and subsequent expansion of the orthosteric binding site upon cannabidiol binding. Finally, changes in the cytoplasmic region and high helix 8 mobility were related to impaired receptor internalization. Together, these results offer a possible explanation to how cannabidiol can directly modulate effects of delta-9-tetrahydrocannabinol on the cannabinoid receptor type 1.