Breast cancer (BC) is the second most prevalent cancer worldwide. Estrogen receptor beta (ERβ) is an essential protein of breast cells to suppress estrogen-induced uncontrolled proliferation. Thus, small molecules that can modulate and enhance ERβ expression would be an effective agent to suppress BC development. Studies showed that cannabinoid (CB), specifically delta-9-tetrahydrocannabinol (Del9THC), can increase the expression of ERβ and inhibits BC cell proliferation. In this study, less psychoactive and structurally similar analogs of Del9THC were chosen as drug candidates and ERβ was targeted as a therapeutic receptor. Delta-8-tetrahydrocannabinol (Del8THC) and delta-4-isotetrahydrocannabinol (Del4isoTHC) were the drug candidates selected on the basis of literature reports, absorption, distribution, metabolism, excretion, and toxicity (ADMET) properties, medicinal chemistry profile, and physicochemical features. Molecular docking simulations were carried out to determine ligand receptor interactions and binding affinity based on free binding energy. To get a better drug, the structural modification was done on Del8THC and generated a new CB analog called Cannabinoid A. Finally, molecular interaction analysis revealed that two CBs and one of their analog interact with the active site residues of ERβ. Therefore, this study revealed a new way to discover novel drug(s) for BC patients.Communicated by Ramaswamy H. Sarma.
Keywords: Breast cancer; cannabinoids; docking simulation; free binding energy; novel drug.