Study of potential inhibition of the estrogen receptor α by cannabinoids using an in silico approach: Agonist vs antagonist mechanism

Rocha-Roa C.; Cortes E.; Cuesta S.A.; Mora J.R.; Paz J.L.; Flores-Sumoza M.; Márquez E.A. · Computers in Biology and Medicine (2023) · DOI: 10.1016/j.compbiomed.2022.106403

Resumen

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.

Instituciones: Universidad Nacional Mayor de San Marcos