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

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 that observed for peptidebased 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. ~~Inhibition of human immunodeficiency virus (HIV-1)l protease leads to loss of viable viral particles in infected cells (1).The x-ray crystal structure of HIV-1 protease (2-9) permits structure-based searches for specific inhibitors (10,11).The dimeric enzyme presents two aspartic acid side chains, one from each monomer, to form a single catalytic site.Two symmetrically disposed p ribbon "flaps" surround the catalytic center and close around peptide-based inhibitors.The instability of peptidomimetic inhibitors in vivo, the inability to deliver them through oral routes, and their poor bio-Health Grant GM 39552.