Computational Approaches for the Discovery of GPER Targeting Compounds

Abstract

Estrogens exert a panel of biological activities mainly through the estrogen receptors α and β, which belong to the nuclear receptor superfamily. Diverse studies have shown that the G protein-coupled estrogen receptor 1 (GPER, previously known as GPR30) also mediates the multifaceted effects of estrogens in numerous pathophysiological events, including neurodegenerative, immune, metabolic, and cardiovascular disorders and the progression of different types of cancer. In particular, GPER is implicated in hormone-sensitive tumors, albeit diverse issues remain to be deeply investigated. As such, this receptor may represent an appealing target for therapeutics in different diseases. The yet unavailable complete GPER crystallographic structure, and its relatively low sequence similarity with the other members of the G protein-coupled receptor (GPCR) family, hamper the possibility to discover compounds able to modulate GPER activity. Consequently, a reliable molecular model of this receptor is required for the design of suitable ligands. To date, convergent approaches involving structure-based drug design and virtual ligand screening have led to the identification of several GPER selective ligands, thus providing important information regarding its mode of action and function. In this survey, we summarize results obtained through computer-aided techniques devoted to the assessment of GPER ligands toward their usefulness in innovative treatments of different diseases.

Keywords: G protein-coupled estrogen receptor 1; drug design; estrogen receptors; ligands; molecular docking; molecular dynamics.