Modelagem e docking molecular de Derlin-1: ligantes naturais e modulação do estresse do retículo endoplasmático em células de câncer de próstata

Abstract

The endoplasmic reticulum (ER) plays a central role in protein synthesis, folding, and quality control. Its homeostasis is maintained by the Unfolded Protein Response and Endoplasmic Reticulum-Associated Degradation pathways, the latter being responsible for the retrotranslocation and degradation of misfolded proteins. Derlin-1 acts as a key component of the retrotranslocation channel in association with the p97/VCP ATPase, being activated by high protein demand. Accordingly, its overexpression has been described in different tumors, including prostate cancer (PCa), in which a strong dependence on proteostasis mechanisms is observed, especially in castration-resistant prostate cancer (CRPC). Indeed, in CRPC there is intense metabolic reprogramming and persistent activation of ER stress, such that Derlin-1 helps sustain transformed cells. In this scenario, the pharmacological modulation of Derlin-1 has proven to be a still poorly explored therapeutic strategy. Natural compounds are historically relevant, especially in oncology, and structural bioinformatics tools, such as homology modeling, docking, and molecular dynamics, combined with ADMET predictions, allow for the rational investigation of their interaction with ligands. Thus, this theoretical framework positions Derlin-1 as a relevant molecular target and explores the phenolic compound 4-nerolidylcatechol as a bioactive and structurally compatible natural candidate for modeling and molecular docking approaches aimed at CRPC.