An Old Target Revisited: Two New Privileged Skeletons and an Unexpected Binding Mode For HIV-Protease Inhibitors

Favored entrance for the privileged. Two inhibitor structures to address the active site of aspartic proteases have been developed. They are equipped with a central hydroxysulfone unit and, alternatively, a pyrrolidine moiety and decorated with rationally designed side chains. The hydroxysulfones bi...

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Published inAngewandte Chemie (International ed.) Vol. 44; no. 20; pp. 3140 - 3144
Main Authors Specker, Edgar, Böttcher, Jark, Lilie, Hauke, Heine, Andreas, Schoop, Andreas, Müller, Gerhard, Griebenow, Nils, Klebe, Gerhard
Format Journal Article
LanguageEnglish
Published Weinheim WILEY-VCH Verlag 13.05.2005
WILEY‐VCH Verlag
Subjects
Binding Sites
Drug Design
Drug Evaluation, Preclinical
HIV protease
HIV Protease Inhibitors - chemical synthesis
HIV Protease Inhibitors - chemistry
Humans
Hydrogen Bonding
inhibitors
Models, Molecular
Molecular Structure
proteins
structure determination
Structure-Activity Relationship
Sulfones - chemical synthesis
Sulfones - chemistry
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Summary:Favored entrance for the privileged. Two inhibitor structures to address the active site of aspartic proteases have been developed. They are equipped with a central hydroxysulfone unit and, alternatively, a pyrrolidine moiety and decorated with rationally designed side chains. The hydroxysulfones bind to HIV protease as expected, whereas the pyrrolidines display a surprising, previously unreported binding mode.
Bibliography:ark:/67375/WNG-88KQD734-Q
istex:19078ABF8EB16EA768C25854ED0A9EFE118E4B6D
ArticleID:ANIE200462643
The authors are grateful to Bayer AG, Wuppertal (Germany), for financial support. The clone of the protease was kindly provided by Prof. Helena Danielson, University of Uppsala, Department of Biochemistry.
Equally contributing authors
ObjectType-Article-1
SourceType-Scholarly Journals-1
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ISSN:1433-7851
1521-3773
DOI:10.1002/anie.200462643