Using a combination of virtual and biomolecular screening, the first selective agonist for GPR30, a G-protein-coupled receptor that is activated by estrogen, has been identified.
Steroid-hormone signalling pathways are modulated by many important drugs, including contraceptives and anticancer drugs such as tamoxifen, a selective oestrogen-receptor modulator. But the development of improved drugs targeting such pathways is hampered by a lack of understanding of why drugs such as tamoxifen can act as antagonists in some tissues and agonists in others. In particular, key questions remain about the nature of the receptors that mediate drug effects. Now, using an efficient combination of virtual and biomolecular screening, Oprea, Prossnitz and colleagues have identified the first selective agonist for GPR30, a G-protein-coupled receptor (GPCR) that has been recently shown to be activated by oestrogen, which will be valuable in clarifying its role in oestrogen signalling.
Traditionally, it has been thought that the effects of steroid hormones are mediated through ligand-activated transcription factors in the nucleus — two oestrogen receptors, ER and ER, in the case of oestrogen. However, in recent years it has become apparent that in addition to genomic effects mediated by such receptors, steroid hormones can activate rapid, non-genomic signalling pathways through other receptors, such as GPR30, which was first linked several years ago to the activation of kinase signalling pathways by the classical oestrogen-receptor agonist oestradiol.
So far though, gaining insight into the role of GPR30 in mediating the effects of oestrogen has been severely limited by the inability to modulate this receptor independently of ER and ER. To address this issue, Bologa et al. set out to discover GPR30-specific ligands. First, they virtually screened a 10,000-compound library (pre-optimized to be enriched in compounds that bind to GPCRs) using a combination of measures of two- and three-dimensional similarity to oestradiol. The 100 highest-scoring compounds in this virtual screen were then screened in a series of novel fluorescence-based cellular assays, which led to the identification of one non-steroidal compound, G-1, that specifically bound to and activated GPR30, but not ER and ER. This compound will facilitate investigation of the in vivo role of GPR30, enhancing understanding of steroid-hormone signalling and potentially opening the door to the discovery of better drugs that target oestrogen receptors.
Peter Kirkpatrick
References
Bologa, C. G. et al. Virtual and biomolecular screening converge on a selective agonist for GPR30. Nature Chem. Biol.2, 207–212 (2006) | Article |
Norman, A. W., Mizwicki, M. T. & Norman, D. G. Steroid-hormone rapid actions, membrane receptors and a conformational ensemble model. Nature Rev. Drug Discov.3, 27–41 (2004) | Article |
and ER
, in the case of oestrogen. However, in recent years it has become apparent that in addition to genomic effects mediated by such receptors, steroid hormones can activate rapid, non-genomic signalling pathways through other receptors, such as GPR30, which was first linked several years ago to the activation of kinase signalling pathways by the classical oestrogen-receptor agonist oestradiol.