STRUCTURE OF A NONPEPTIDE INHIBITOR COMPLEXED WITH HIV-1 PROTEASE - DEVELOPING A CYCLE OF STRUCTURE-BASED DRUG DESIGN

A stable, non-peptide inhibitor of the protease from type 1 human immu nodeficiency virus has been developed, and the stereochemistry of bind ing defined through crystallographic three-dimensional structure deter mination. The initial compound, haloperidol, was discovered through co mputational screening of the Cambridge Structural Database using a sha pe complementarity algorithm. The subsequent modification is a non-pep tidic lateral lead, which belongs to a family of compounds with well c haracterized 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 peptide-based inhibito rs. A variant of the protease cocrystallized with this inhibitor shows binding in the manner predicted during the initial computer-based sea rch. The structures provide the context for subsequent synthetic modif ications of the inhibitor.