Structure of a non-peptide inhibitor complexed with HIV-1 protease. Developing a cycle of structure-based drug design.
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Rutenber E, Fauman EB, Keenan RJ, Fong S, Furth PS, Ortiz de Montellano PR, Meng E, Kuntz ID, DeCamp DL, Salto R, et al.
Structure of a non-peptide inhibitor complexed with HIV-1 protease. Developing a cycle of structure-based drug design.
J Biol Chem. 1993 Jul 25;268(21):15343-6.
- PubMed ID
- 8340363 [ View in PubMed]
- 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.