Inhibition of human androgen receptor by delta 9-tetrahydro-cannabinol and cannabidiol related to reproductive dysfunction: A computational study

There have been conflicting reports on the impact of Cannabis sativa impact on reproductive function. Hence this study was aimed to ascertain the impact of tetrahydrocannabinol (THC) and cannabidiol (CBD) binding affinity on human androgen receptor (AR) via computational molecular dynamic simulation. The human AR coordinate in this study is derived from human AR in complex with the ligand metribolone (R18) (PBD ID: 1E3G) template using (MODELER version. 9.15). CBD (PubChem CID: 644019), and THC (PubChem CID: 16078) 2D structures were retrieved from PubChem and docked (Autodock-Vina inbuilt in PyMol into the active site of human AR using the coordinates of the co-crystalized ligand (R18). All atomic representations in this study were created using visual molecular dynamics (VMD) tools. The result revealed that neither CBD nor THC bear significant 2D similarity with R18. Despite the diversity within the chemical space, both CBD and THC poses bond flexibility required to bind avidly to AR with the docking scores comparable to R18. In fully bound state, the three compounds engage the AR pocket hydrophobic residues such as L701, L704, and L707, and aromatic residues such as F764. Polar contacts with T877 observed in R18 bound state is avoided in the THC and CBD bound states. Moreso, the results revealed that CBD has lesser binding energy compared to THC and R18 compound which serves as standard. This study hypothesized that CBD and THC binds complimentarily to the pocket AR, indicating a likely inhibition of reproductive function and prostate cancer progression.