In silico exploration of pyrocannabinoid interactions with key protein targets.

Cannabinoids, particularly those derived from cannabis, attract considerable attention in recent years for their therapeutic potential in treating various diseases and ailments. In this study, we identify cannabinoid byproducts that result from the combustion of cannabidiol-henceforth referred to as pyrocannabinoids-and employ molecular docking simulations to investigate their interactions with key protein targets implicated in different physiological processes. Specifically, we focus on peroxisome proliferator-activated receptor gamma, p21-activated kinase 1, CB1, CB2, and GPR119 proteins, elucidating the binding modes and affinities of pyrocannabinoid byproducts to these receptors. This investigation is done in collaboration with Real Isolates LLC. Our findings reveal diverse ligand-protein interactions, with some pyrocannabinoids displaying favorable binding energies and stable ligand-protein complexes. However, variations in binding affinities across different proteins underscore the complex pharmacological profiles of the pyrocannabinoids. Furthermore, the prediction of adsorption, distribution, metabolism, excretion and toxicity properties highlights both promising and concerning aspects of cannabinoid pharmacokinetics, emphasizing the need for thorough preclinical evaluation. Additionally, our investigation into potential metabolic sites using cytochrome P450 enzymes provides insights into cannabinoid metabolites. Overall, our study contributes to the understanding of pyrocannabinoid pharmacology and informs the rational design of pyrocannabinoid-based therapeutics. Further experimental validation is warranted to translate these findings into clinically relevant applications. Supplementary Information: The online version contains supplementary material available at 10.1007/s40203-025-00391-9.