Discovery of new inhibitors of aldo-keto reductase 1C1 by structure-based virtual screening

Aldo-keto reductase 1C1 is a hydroxysteroid dehydrogenase that inactivates progesterone by converting it to 20α-hydroxyprogesterone. It also inactivates 3α,5α-tetrahydroprogesterone, an allosteric modulator of the γ-aminobutyric acid receptor that has anaesthetic, analgesic, anxiolytic and anti-convulsant effects. Inhibitors of aldo-keto reductase 1C1 are thus very interesting as potential agents for the treatment of endometrial cancer, premenstrual syndrome, catamenial epilepsy, and depressive disorders, and for the maintenance of pregnancy. We have used the molecular docking program eHiTS for virtual screening of 1990 compounds from the National Cancer Institute “Diversity Set”. Fifty compounds with the highest predicted binding energies were then evaluated in vitro. Three structurally diverse hits were obtained that inhibit aldo-keto reductase 1C1 in the low micromolar range of IC50 values. These hits represent promising starting points for structural optimization in hit-to-lead development.