Estrogens affect the physiology of many tissues and organs mostly via regulating the transcription of estrogen target genes through two estrogen receptor (ER) subtypes, ERα and ERβ. Intensive pharmaceutical research led to the development of Raloxifen (RAL) and Tamoxifen (TAM), now in clinical use as EVISTA and NOLVADEX respectively, displaying agonist or antagonist behaviour, depending on the tissue and thus termed as Selective Estrogen Modulatiops (SERMS). X-ray structures of ER-ligand complexes have revealed the key role of the conformation of the C-terminal Helix of ER Ligand Binding Domain (LBD), Helix-12, which can be associated to the agonist, antagonist or partial agonist activity of a ligand.

The new emerging computational tools can subsequently use these structural data for in silico modeling of ligand-receptor association (docking) in order to predict the activity of new ER ligands prior to their synthesis. In our group we explore the estrogenic activity of different synthetic as well as plant derived molecules (phytoestrogens). Moreover the efficiency of different computational approaches in predicting binding affinities of our newly synthesized analogues of RAL and the agonist/antagonist activity of well known ER binders are investigated for structure based drug design.

Selected Publications

Alexi, X., Kasiotis, K.M., Fokialakis, N., Lambrinidis, G., Meligova, A.K., Mikros, E., Haroutounian, S.A., Alexis, M.N. Differential estrogen receptor subtype modulators: Assessment of estrogen receptor subtype-binding selectivity and transcription-regulating properties of new cycloalkyl pyrazoles (2009) Journal of Steroid Biochemistry and Molecular Biology, 117 (4-5), pp. 159-167.
DOI: 10.1016/j.jsbmb.2009.09.006

Papoutsi, Z., Kassi, E., Fokialakis, N., Mitakou, S., Lambrinidis, G., Mikros, E., Moutsatsou, P. Deoxybenzoins are novel potent selective estrogen receptor modulators (2007) Steroids, 72 (9-10), pp. 693-704.
DOI: 10.1016/j.steroids.2007.05.010

Lambrinidis, G., Halabalaki, M., Katsanou, E.S., Skaltsounis, A.-L., Alexis, M.N., Mikros, E. The estrogen receptor and polyphenols: Molecular simulation studies of their interactions, a review (2006) Environmental Chemistry Letters, 4 (3), pp. 159-174.
DOI: 10.1007/s10311-006-0065-y

Halabalaki, M., Alexi, X., Aligiannis, N., Lambrinidis, G., Pratsinis, H., Florentin, I., Mitakou, S., Mikros, E., Skaltsounis, A.-L., Alexis, M.N. Estrogenic activity of isoflavonoids from Onobrychis ebenoides (2006) Planta Medica, 72 (6), pp. 488-493.
DOI: 10.1055/s-2005-916261

Fokialakis, N., Lambrinidis, G., Mitsiou, D.J., Aligiannis, N., Mitakou, S., Skaltsounis, A.-L., Pratsinis, H., Mikros, E., Alexis, M.N. A new class of phytoestrogens: Evaluation of the estrogenic activity of deoxybenzoins (2004) Chemistry and Biology, 11 (3), pp. 397-406.
DOI: 10.1016/j.chembiol.2004.02.014