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.

Binding of Androgen- and Estrogen-Like Flavonoids to Their Cognate (Non)Nuclear Receptors: A Comparison by Computational Prediction

“…Other molecules having an agonist/antagonist action towards ERs are known to bind GPER, like, for instance, tamoxifen [ 43 ], raloxifene [ 44 ], bisphenol A [ 45 ], and also plant derived flavonoids, such as genistein [ 46 , 47 ], quercetin [ 48 ], and resveratrol [ 49 ]. There is, notably, an important structural heterogeneity among molecules that are able to target GPER, clearly hampering the prediction and identification of new ligands [ 50 ].…”

Expression and estrogen regulation of G protein‑coupled estrogen receptor in human glioblastoma cells

“…In addition, the highest binding energies for E2 and G1 were detected in the human GPCR-based model (6LFL), suggesting that this is the most realistic model. In this regard, Grande et al ( 64 ) reported that the interaction of G1 and E2 with GPER occurs in an intracellular region. However, a molecular docking for deciphering the GPER agonist interactions reported that a ligand could be recognized at different binding sites depending on the used structural GPER conformation ( 65 ).…”

Identification of a human estrogen receptor α tetrapeptidic fragment with dual antiproliferative and anti-nociceptive action

“…It works in concert with ERα and its alternative spliced isoform ERα36, as well as with the growth factor receptors EGFR and IGF-1R 30 – 32 . As strongly suggested by staining and docking studies, the pharmacological effects of ERα17p result from its binding within the ligand-binding site of GPER (Kd in the micromolar range) 23 , 33 . Remarkably, ERα17p induces at low doses and in short times (1.5 mg/kg body weight, three times a week for four weeks) a decrease of about 50% of the size of xenografted triple negative breast tumors, in mice 21 .…”