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J. Biol. Chem., Vol. 268, Issue 21, 15343-15346, 07, 1993

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

E Rutenber, EB Fauman, RJ Keenan, S Fong, PS Furth, PR Ortiz de Montellano, E Meng, ID Kuntz, DL DeCamp and R Salto
Department of Biochemistry and Biophysics, University of California, San Francisco 94143-0448.

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.
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