title: Protein structure-based design of potent orally bioavailable, nonpeptide inhibitors of human immunodeficiency virus protease.
abstract: A class of potent nonpeptidic inhibitors of human immunodeficiency virus protease has been designed by using the three-dimensional structure of the enzyme as a guide. By employing iterative protein cocrystal structure analysis, design, and synthesis the binding affinity of the lead compound was incrementally improved by over four orders of magnitude. An inversion in inhibitor binding mode was observed crystallographically, providing information critical for subsequent design and highlighting the utility of structural feedback in inhibitor optimization. These inhibitors are selective for the viral protease enzyme, possess good antiviral activity, and are orally available in three species.
authors.affiliation: Agouron Pharmaceuticals, Inc., San Diego, CA 92121, USA.
authors.forename: S H
authors.initials: SH
authors.lastname: Reich
authors.forename: M
authors.initials: M
authors.lastname: Melnick
authors.forename: J F
authors.initials: JF
authors.lastname: Davies
authors.forename: K
authors.initials: K
authors.lastname: Appelt
authors.forename: K K
authors.initials: KK
authors.lastname: Lewis
authors.forename: M A
authors.initials: MA
authors.lastname: Fuhry
authors.forename: M
authors.initials: M
authors.lastname: Pino
authors.forename: A J
authors.initials: AJ
authors.lastname: Trippe
authors.forename: D
authors.initials: D
authors.lastname: Nguyen
authors.forename: H
authors.initials: H
authors.lastname: Dawson
mesh_terms: D000284:Administration, Oral; D000595:Amino Acid Sequence; D000818:Animals; D001549:Benzamides / Q000737:chemistry; D001682:Biological Availability; D004285:Dogs; D015195:Drug Design; D004341:Drug Evaluation; D006678:HIV / Q000187:drug effects* / Q000201:enzymology; D017320:HIV Protease Inhibitors / Q000008:administration & dosage / Q000737:chemistry* / Q000493:pharmacokinetics / Q000494:pharmacology*; D000882:Haplorhini; D051379:Mice; D008958:Models, Molecular; D008969:Molecular Sequence Data; D051381:Rats; D013045:Species Specificity; D013329:Structure-Activity Relationship
chemical_list: D001549:Benzamides; D017320:HIV Protease Inhibitors