Cannabidiol binding and negative allosteric modulation at the cannabinoid type 1 receptor in the presence of delta-9-tetrahydrocannabinol: An In Silico study

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.近期相关研究提出讨论：大麻二酚（cannabidiol）可作为1型大麻素受体（cannabinoid type 1 receptor）的负变构调节剂（negative allosteric modulator）。本研究采用计算方法，探究大麻二酚对Δ9-四氢大麻酚（delta-9-tetrahydrocannabinol）在1型大麻素受体上产生的调控效应，以及其直接阻断该受体的可能性。我们提出一个推定的变构结合位点，该位点位于受体的N端区域，与正构结合位点（orthosteric binding site）存在部分重叠。分子动力学模拟（molecular dynamics simulations）结果显示，大麻二酚结合后会引发协同运动：螺旋1与螺旋2向外旋转，随后正构结合位点发生扩张。此外，胞质区的结构变化以及螺旋8的高迁移率与受体内吞（receptor internalization）受损相关。综上，本研究结果为大麻二酚如何直接调控Δ9-四氢大麻酚在1型大麻素受体上的作用提供了可行的解释。