title: Additivity in the analysis and design of HIV protease inhibitors.
abstract: We explore the applicability of an additive treatment of substituent effects to the analysis and design of HIV protease inhibitors. Affinity data for a set of inhibitors with a common chemical framework were analyzed to provide estimates of the free energy contribution of each chemical substituent. These estimates were then used to design new inhibitors whose high affinities were confirmed by synthesis and experimental testing. Derivations of additive models by least-squares and ridge-regression methods were found to yield statistically similar results. The additivity approach was also compared with standard molecular descriptor-based QSAR; the latter was not found to provide superior predictions. Crystallographic studies of HIV protease-inhibitor complexes help explain the perhaps surprisingly high degree of substituent additivity in this system, and allow some of the additivity coefficients to be rationalized on a structural basis.
authors.affiliation: Center for Advanced Research in Biotechnology, UMBI, 9600 Gudelsky Drive, Rockville, Maryland 20850, USA.
authors.forename: Robert N
authors.initials: RN
authors.lastname: Jorissen
authors.forename: G S Kiran Kumar
authors.initials: GS
authors.lastname: Reddy
authors.forename: Akbar
authors.initials: A
authors.lastname: Ali
authors.forename: Michael D
authors.initials: MD
authors.lastname: Altman
authors.forename: Sripriya
authors.initials: S
authors.lastname: Chellappan
authors.forename: Saima G
authors.initials: SG
authors.lastname: Anjum
authors.forename: Bruce
authors.initials: B
authors.lastname: Tidor
authors.forename: Celia A
authors.initials: CA
authors.lastname: Schiffer
authors.forename: Tariq M
authors.initials: TM
authors.lastname: Rana
authors.forename: Michael K
authors.initials: MK
authors.lastname: Gilson
mesh_terms: D001665:Binding Sites; D002219:Carbamates / Q000138:chemical synthesis / Q000494:pharmacology; D003461:Crystallography; D015195:Drug Design; D031541:Fluorescence Resonance Energy Transfer; D016333:HIV Protease / Q000187:drug effects / Q000378:metabolism; D017320:HIV Protease Inhibitors / Q000138:chemical synthesis* / Q000494:pharmacology; D007700:Kinetics; D008958:Models, Molecular; D021281:Quantitative Structure-Activity Relationship
chemical_list: D002219:Carbamates; D017320:HIV Protease Inhibitors; D016333:HIV Protease