Conformational Study of Cannabinoid Docking to Cannabinoid Receptor 1 (CB1) via Linear and Nonlinear Circular Dichroism

The exact mechanism of binding of (-)-trans-Δ9-tetrahydrocannabinol (the main psychoactive component of marijuana) to the cannabinoid receptor, CB1, is unknown. Conformational information of the cannabinoids may give insight to this mechanism and the elicited effects of consumption. Herein, we report on the theoretical conformational study of Δ9-tetrahydrocannabinol (Δ9-THC) and cannabidiol (CBD), the psychoactive and a non-psychoactive compound found in marijuana, respectively, using electronic circular dichroism (ECD) and two-photon circular dichroism (TPCD). The compounds were optimized in vacuo and in the receptor site using DFT and B3LYP with the 6-311G** basis set and spectra were calculated using the same level of theory, but with the 6-311++G** basis set. First, we present and discuss the comparison of experimental and theoretical ECD spectra of (-)-trans-Δ9-THC and CBD in methanol solution in order to corroborate our theoretical approach. Second, we show, theoretically, the enhanced sensitivity of TPCD compared with ECD to conformational changes of cannabinoids upon docking, giving rise to a potential application in vivo. Finally, the comparative analysis of the theoretical TPCD spectra of Δ9-THC and CBD show distinct fingerprints in the far-UV region for two conformers of each molecule, which may help to understand the specific binding mechanisms of these species to the cannabinoid receptors and to describe the difference in psychological effects upon consumption. Our results show the complementarity of these two spectroscopic techniques and the potential of TPCD to determine the conformational changes of cannabinoids upon docking to the CB1 receptor.