Exploring Biological Targets of Magnolol and Honokiol and their Nature-Inspired Synthetic Derivatives: In Silico Identification and Experimental Validation of Estrogen Receptors

In this work, we describe the results of a computational investigation aimed at identifying potential biological targets of honokiol, magnolol and a series of synthetic prodrug derivatives obtained through esterification of the free hydroxyl groups. The ligand-based and structure-based analyses revealed that these compounds potentially interact with several biological targets, some of which are known while others are new. Honokiol, magnolol, and three of the newly synthesized derivatives may bind to estrogen receptors ER alpha and ER beta. Biological testing confirmed that these compounds modulate estrogen-regulated transcriptional activity mediated by ER alpha or ER beta with potencies in the nanomolar range. In particular, magnolol and one of its derivatives (10) behaved as partial antagonists of ER alpha and ER beta, while compounds 8 and 11 behaved as partial agonists. These findings validate the computational predictions and shed light on the mechanism of action of these natural compounds, paving the way for further investigation in the context of targeted therapies.