17-β-Hydroxysteroid dehydrogenase type 1: computational design of active site inhibitors targeted to the Rossmann fold

• Published in: Chemico-biological interactions Vol. 143; pp. 481 - 491
• Main Authors: Brown, William M, Metzger, Louis E, Barlow, Jeremy P, Hunsaker, Lucy A, Deck, Lorraine M, Royer, Robert E, Vander Jagt, David L
• Format: Journal Article
• Language: English
• Published: Ireland Elsevier Ireland Ltd 01-02-2003
• Subjects: 17-Hydroxysteroid Dehydrogenases - antagonists & inhibitors; 17-Hydroxysteroid Dehydrogenases - chemistry; 17-Hydroxysteroid Dehydrogenases - metabolism; 17-β-Hydroxysteroid dehydrogenases type 1; Binding Sites; Breast cancer; Enzyme Inhibitors - pharmacology; Gossypol derivatives; Inhibition; Kinetics; Rossmann fold; Breast cancer; Rossmann fold; 17-β-Hydroxysteroid dehydrogenases type 1; Inhibition; Gossypol derivatives
• ISSN: 0009-2797; 1872-7786
• DOI: 10.1016/S0009-2797(02)00184-9

17-β-Hydroxysteroid dehydrogenase type 1 (17βHSD1), also called estradiol dehydrogenase, catalyzes the NADPH-dependent reduction of the weak estrogen, estrone, into the more potent estrogen, 17-β-estradiol. 17βHSD1 is an attractive drug target in hormone-sensitive breast cancer. Past efforts to develop selective inhibitors of 17βHSD1 have focused on design of substrate analogs. It is challenging to develop steroid analogs that are devoid of any undesired biological activity. 17βHSD1 is a member of the short-chain dehydrogenase/reductase (SDR) superfamily that includes many hydroxysteroid dehydrogenases. Members of the SDR family bind NAD(P)(H) in a motif that is a modified Rossmann fold. We demonstrated previously that the Rossmann folds of classical dehydrogenases can be selectively inhibited by derivatives and analogs of the natural product gossypol. In this study, we have addressed the question whether the modified Rossmann fold in 17βHSD1 is a target for identification of lead compounds for structure-based drug design. 17βHSD1 was purified from human placenta. 17βHSD1 is inhibited by derivatives of gossypol with dissociation constants as low as 2 μM. Inhibition is competitive with the binding of cofactor. Molecular modeling studies using the published coordinates of human 17βHSD1 suggest that these inhibitors occupy the modified Rossmann fold at the nicotinamide end of the dinucleotide-binding site, extending towards the substrate site. A computational approach was used to design potential new inhibitors of 17βHSD1. The results suggest not only that derivatives of gossypol represent attractive lead compounds for structure-based drug design but also suggest that appropriate incorporation of a substrate analog into the design of these Rossmann fold inhibitors may provide pan-active site inhibitors that span the cofactor and substrate site, potentially offering specificity and increased potency.