Recent Advances in the Rationale Design of GPER Ligands

C.      Rosano; R.      Lappano; M.      F. Santolla; M.      Ponassi; A.      Donadini; M.      Maggiolini

doi:10.2174/0929867311209066199

Abstract

G-Protein Coupled Receptor (GPCR) superfamily, which comprises approximately 900 members, is the largest family of protein targets with proven therapeutic value. Although at least 500 GPCRs have been identified as therapeutically relevant, only thirteen GPCRs have been structurally characterized in apo-form or in complex with ligands. GPCRs share relatively low sequence similarity making hard the process of homology modelling, nevertheless some successful hits have been determined. Recently, the G-proteincoupled estrogen receptor 1 (GPER, formerly known as GPR30) has attracted increasing interest due to its ability in mediating estrogen signaling in different normal and cancer tissues. In this regard, the identification of selective GPER ligands has provided valuable tools in order to differentiate the specific functions elicited by this novel estrogen receptor respect to those exerted by the classical estrogen receptors (ERs). In this review, we focus on GPER examining “in silico” docking simulations and evaluating the different binding modes of diverse natural and synthetic ligands.

Keywords: GPR30/GPER, estrogens, antiestrogens, GPCRs, receptor, agonists/antagonists, atomic structures, “in silico” docking simulations, homology modelling, small molecules ligands, virtual screening, binding modes