Structural highlights
3gmd is a 8 chain structure with sequence from Lk3 transgenic mice. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
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| Ligands: | , , |
| Gene: | Hsd11, Hsd11b1, HSD11L (LK3 transgenic mice) |
| Activity: | 11-beta-hydroxysteroid dehydrogenase, with EC number 1.1.1.146 |
| Resources: | FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT |
Function
[DHI1_MOUSE] Catalyzes reversibly the conversion of cortisol to the inactive metabolite cortisone.
Publication Abstract from PubMed
Indole-pyrrolidines were identified as inhibitors of 11beta-hydroxysteroid dehydrogenase type 1 (11beta-HSD1) by high-throughput screening. Optimisation of the initial hit through structure-based design led to 7-azaindole-derivatives, with the best analogues displaying single digit nanomolar IC(50) potency. The modeling hypotheses were confirmed by solving the X-ray co-crystal structure of one of the lead compounds. These compounds were selective against 11beta-hydroxysteroid dehydrogenase type 2 (selectivity ratio >200) and exhibited good inhibition of 11beta-HSD1 (IC(50)<1muM) in a cellular model (3T3L1 adipocytes).
Structure-based design of 7-azaindole-pyrrolidine amides as inhibitors of 11beta-hydroxysteroid dehydrogenase type I.,Valeur E, Christmann-Franck S, Lepifre F, Carniato D, Cravo D, Charon C, Bozec S, Musil D, Hillertz P, Doare L, Schmidlin F, Lecomte M, Schultz M, Roche D Bioorg Med Chem Lett. 2012 Sep 15;22(18):5909-14. doi:, 10.1016/j.bmcl.2012.07.070. Epub 2012 Jul 31. PMID:22901389[1]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
References
- ↑ Valeur E, Christmann-Franck S, Lepifre F, Carniato D, Cravo D, Charon C, Bozec S, Musil D, Hillertz P, Doare L, Schmidlin F, Lecomte M, Schultz M, Roche D. Structure-based design of 7-azaindole-pyrrolidine amides as inhibitors of 11beta-hydroxysteroid dehydrogenase type I. Bioorg Med Chem Lett. 2012 Sep 15;22(18):5909-14. doi:, 10.1016/j.bmcl.2012.07.070. Epub 2012 Jul 31. PMID:22901389 doi:10.1016/j.bmcl.2012.07.070
