In silico investigation of cannabinoids from Cannabis sativa leaves as a potential anticancer drug to inhibit MAPK-ERK signaling pathway and EMT induction.

UNLABELLED: Genes related to MAPK-ERK signaling pathways, and epithelial-mesenchymal transition induction is evolutionarily conserved and has crucial roles in the regulation of important cellular processes, including cell proliferation. In this study, six cannabinoids from  Cannabis sativa  were docked with MAPK-ERK signaling pathways to identify their possible binding interactions. The results showed that all the cannabinoids have good binding affinities with the target proteins. The best binding affinities were MEK- tetrahydrocannabinol (- 8.8 kcal/mol) and P13k-cannabinol (- 8.5 kcal/mol). The root mean square deviation was calculated and used two alternative variants (rmsd/ub and rmsd/lb) and the values of rmsd/lb fluctuated 8.6-2.0 Å and for rmsd/ub from 1.0 to 2.0 Å that suggests the cannabinoids and protein complex are accurate and cannot destroy on binding. The study analyzed the pharmacokinetic and drug-likeness properties of six cannabinoids from C. sativa leaves using the SwissADME web tool. Lipinski's rule of five was used to predict drug-likeness and showed that all compounds have not violated it and the total polar surface area of cannabinoids was also according to Lipinski's rule that is benchmarked of anticancer drugs. Cannabinoids are meet the requirements of leadlikeness and synthetic accessibility values showed they can be synthesized. The molecular weight, XLOGP3, solubility (log S), and flexibility (FLEX) are according to the bioavailability radar. The bioavailability score and consensus Log Po/w fall within the acceptable range for the suitable drug. Pharmacokinetics parameters showed that cannabinoids cannot cross the blood-brain barrier, have high GI absorption as well as cannabinoids are substrates of (CYP1A2, CYP2C19, CYP2C9, CYP2D6, and CYP3A4) but no substrate of P-glycoprotein. Based on these findings, the study suggests that cannabinoids are suitable drugs that could be used as effective inhibitors for target proteins involved in cancer pathways. Among the six cannabinoids, cannabinol and tetrahydrocannabinol exerted maximum binding affinities with proteins of MAPK-ERK signaling pathways, and their pharmacokinetics and drug-likeness-related profiles suggest that these cannabinoids could be superlative inhibitors in cancer treatment. Further in vitro, in vivo, and clinical studies are needed to explore their potential in cancer treatment.

SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1007/s40203-024-00213-4.