Premium
A concerted, rational design of type 1 17β‐hydroxysteroid dehydrogenase inhibitors: estradiol‐adenosine hybrids with high affinity
Author(s) -
Qiu Wei,
Campbell Robert L.,
Gangloff Anne,
Dupuis Philippe,
Boivin Roch P.,
Tremblay Martin R.,
Poirier Donald,
Lin ShengXiang
Publication year - 2002
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fj.02-0026fje
Subject(s) - enzyme , cofactor , stereochemistry , chemistry , dehydrogenase , substrate (aquarium) , linker , biochemistry , hydroxysteroid dehydrogenases , hydroxysteroid dehydrogenase , biology , ecology , computer science , operating system
Human estrogenic 17β‐hydroxysteroid dehydrogenase (17β‐HSD type 1) catalyzes the final step in the synthesis of active estrogens that stimulate the proliferation of breast cancer cells. Based on the initial premise to make use of the binding energies of both the substrate and cofactor sites, and molecular modeling starting from the enzyme structure, several estradiol‐adenosine hybrids were designed and synthesized. Among these hybrids, EM‐1745 with a linker of 8‐CH 2 groups is proved to be the best competitive inhibitor with a K i of 3.0 ± 0.8 nM. The crystal structure of the EM‐1745 enzyme complex at 1.6 Å provides evidence at atomic resolution of strong interactions between both the steroid and cofactor moieties and the enzyme molecule, as illustrated by a σAweighted 2Fo‐Fc electron density map contoured at 3.0 σ. The substrate entry loop is further stabilized in this complex compared with previous complexes of the enzyme. These results confirm our initial strategy of combining studies of structural biology and enzyme mechanism in the inhibitor design, which may be applied to other steroidogenic enzymes involved in human diseases.