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J Biol Chem. 1993 Jul 25;268(21):15343-6.

Structure of a non-peptide inhibitor complexed with HIV-1 protease. Developing a cycle of structure-based drug design.

Author information

1
Department of Biochemistry and Biophysics, University of California, San Francisco 94143-0448.

Abstract

A stable, non-peptide inhibitor of the protease from type 1 human immunodeficiency virus has been developed, and the stereochemistry of binding defined through crystallographic three-dimensional structure determination. The initial compound, haloperidol, was discovered through computational screening of the Cambridge Structural Database using a shape complementarity algorithm. The subsequent modification is a non-peptidic lateral lead, which belongs to a family of compounds with well characterized pharmacological properties. This thioketal derivative of haloperidol and a halide counterion are bound within the enzyme active site in a mode distinct from the observed for peptide-based inhibitors. A variant of the protease cocrystallized with this inhibitor shows binding in the manner predicted during the initial computer-based search. The structures provide the context for subsequent synthetic modifications of the inhibitor.

PMID:
8340363
[Indexed for MEDLINE]
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