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.
Highlights
The multifaceted responses to estrogens are principally mediated by the estrogen receptors (ERs) α and β, which act as transcription factors by binding to estrogen response elements (EREs) located in the promoter regions of target genes [1]
G protein estrogen receptor (GPER) modulates signaling processes leading to the transcription of genes promoting tumor growth in vitro and in vivo, such as calcium mobilization, cAMP synthesis, the cleavage of matrix metalloproteinases, the transactivation of epidermal growth factor receptor (EGFR) and the activation of PI3K and MAPK transduction pathways [2,3,4,5,6,7,8,9,10,11]
Molecular docking on GPER structures extracted from all-atom molecular dynamics (MD) has demonstrated [48] that the natural polyphenol (–)-epicatechin has the ability to anchor to this receptor with a binding mode similar to the agonist G-1
Summary
The multifaceted responses to estrogens are principally mediated by the estrogen receptors (ERs) α and β, which act as transcription factors by binding to estrogen response elements (EREs) located in the promoter regions of target genes [1]. Considering the interest to identify specific GPER ligands to decipher its unique potential, several successful efforts have been made during the last few years [19,20,21,22,23,24,25]. In this context, it should be mentioned the intriguing discovery of the indole derivative MIBE, which has the property of binding to and antagonizing the effects of both GPER and ER, representing a useful tool toward more comprehensive approaches in estrogen-dependent tumors [22]. The results obtained by application of computational techniques are summarized toward their adoption as starting point for the design and development of novel active agents
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