Breast cancer is the main cancer type with more than 2.2 million cases in 2020, and is the principal cause of death in women; with 685000 deaths in 2020 worldwide. The estrogen receptor is involved at least in 70% of breast cancer diagnoses, and the agonist and antagonist properties of the drug in this receptor play a pivotal role in the control of this illness. This work evaluated the agonist and antagonist mechanisms of 30 cannabinoids by employing molecular docking and dynamic simulations. Compounds with docking scores < -8 kcal/mol were analyzed by molecular dynamic simulation at 300 ns, and relevant insights are given about the protein's structural changes, centered on the helicity in alpha-helices H3, H8, H11, and H12. Cannabicitran was the cannabinoid that presented the best relative binding-free energy (-34.96 kcal/mol), and based on rational modification, we found a new natural-based compound with relative binding-free energy (-44.83 kcal/mol) better than the controls hydroxytamoxifen and acolbifen. Structure modifications that could increase biological activity are suggested.
Keywords: Cannabinoids; Drug discovery; Estrogen receptor alpha; Molecular modelling; Structure-activity relationship.
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