Structure of a non-peptide inhibitor complexed with HIV-1 protease. Developing a cycle of structure-based drug design.
Rutenber E,
Fauman EB,
Keenan RJ,
Fong S,
Furth PS,
Ortiz de Montellano PR,
Meng E,
Kuntz ID,
DeCamp DL,
Salto R, et al.
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.
PMID: 8340363 [PubMed - indexed for MEDLINE]