Pharmacy Department, Faculty of Chemistry, Pontificia Universidad Católica de Chile, Santiago, Chile.
Organic Chemistry Department, Faculty of Chemistry, Pontificia Universidad Católica de Chile, Santiago, Chile.
PLoS One. 2019 Jul 23;14(7):e0220025. doi: 10.1371/journal.pone.0220025. eCollection 2019.
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.
最近的证据引发了讨论，即大麻二酚可能作为大麻素 1 型受体的负变构调节剂发挥作用。在这里，我们使用计算方法研究了大麻二酚对大麻素受体 1 中 δ-9-四氢大麻酚的作用的调制以及直接受体阻断的可能性。我们提出了一个假定的变构结合位点，该位点位于受体的 N 端区域，部分重叠于正位结合位点。分子动力学模拟揭示了涉及螺旋 1 和 2 的向外旋转以及大麻二酚结合后正位结合位点的后续扩张的协调运动。最后，细胞质区域的变化和高螺旋 8 的流动性与受体内化受损有关。总之，这些结果提供了一种可能的解释，即大麻二酚如何直接调节大麻素 1 型受体上 δ-9-四氢大麻酚的作用。
