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Improved structure-activity relationship analysis of HIV-1 protease inhibitors using interaction kinetic data
Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Biochemistry. Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Biochemistry and Organic Chemistry, Biochemistry.
Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Biochemistry. Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Biochemistry and Organic Chemistry, Biochemistry.
2004 (English)In: Journal of Medicinal Chemistry, ISSN 0022-2623, E-ISSN 1520-4804, Vol. 47, no 24, 5953-61 p.Article in journal (Refereed) Published
Abstract [en]

Despite the availability of large amounts of data for HIV-protease inhibitors and their effectiveness with wild type and resistant enzyme, there is limited knowledge about how this and other information can be systematically applied to the development of new antiviral compounds. To identify in vitro parameters that correlate with the efficacy of HIV inhibitors in cell culture, the relationships between inhibition, interaction kinetic, and cell culture parameters for HIV-1 protease inhibitors were analyzed. Correlation, cluster, and principal component analysis of data for 37 cyclic and linear compounds revealed that the affinities (K(D)) determined from SPR-biosensor binding studies correlated better to cell culture efficacy (ED(50)) than that of the inhibition constants (K(i)), indicating that the conventional use of K(i) values for structure-activity relationship analysis of HIV-1 inhibitors should be seriously reconsidered. The association and dissociation kinetic rate constants (k(on) and k(off)) alone showed weak correlations with ED(50) values. However, ED(50) values were most related to the free enzyme concentration in the viral particle ([E]), calculated from the rate constants and the total enzyme concentration in a viral particle. A structure-activity relationship analysis of the current data set was found to be valid for all classes of compounds analyzed. In summary, use of affinity, based on interaction kinetic rate constants, rather than inhibition constants, and theoretical consideration of the physiological conditions in the virus particle provide improved structure-activity relationship analysis of HIV-1 protease inhibitors.

Place, publisher, year, edition, pages
2004. Vol. 47, no 24, 5953-61 p.
Keyword [en]
Biosensing Techniques, Cells; Cultured, Cluster Analysis, HIV Protease/*chemistry/metabolism, HIV Protease Inhibitors/*chemistry/classification/pharmacology, HIV-1/*chemistry/drug effects, Kinetics, Principal Component Analysis, Quantitative Structure-Activity Relationship, Virus Replication/drug effects
National Category
Biochemistry and Molecular Biology
Identifiers
URN: urn:nbn:se:uu:diva-72875DOI: 10.1021/jm0499110PubMedID: 15537350OAI: oai:DiVA.org:uu-72875DiVA: diva2:100786
Available from: 2006-03-01 Created: 2006-03-01 Last updated: 2017-12-14Bibliographically approved
In thesis
1. Interaction Characteristics of Viral Protease Targets and Inhibitors: Perspectives for drug discovery and development of model systems
Open this publication in new window or tab >>Interaction Characteristics of Viral Protease Targets and Inhibitors: Perspectives for drug discovery and development of model systems
2003 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

Viral proteases are important targets for anti-viral drugs. Discovery of protease inhibitors as anti-viral drugs is aided by an understanding of the interactions between viral protease and inhibitors. This thesis addresses the characterization of protease-inhibitor interactions for application to drug discovery and model system development.

The choice of a relevant target is essential to molecular interaction studies. Therefore, full-length NS3 protein of hepatitis C virus (HCV) was obtained, providing a more relevant target and a better model for the development of HCV protease inhibitors. In addition, resistance to anti-viral drugs, a serious problem in the treatment of AIDS, prompted the investigation of resistant variants of human immunodeficiency virus (HIV) protease.

Drug resistance was initially explored by characterization of the interactions between a series of closely related inhibitors and resistant variants of HIV protease, using an inhibition assay to determine the inhibition dissociation constants (Ki). The relationship between structure, activity and resistance profiles was not clarified, indicating that the effect of structural changes in the inhibitors and the protease are not predictable and must be analyzed case wise. It was proposed that additional kinetic characterization of the interactions was required and a biosensor-based method allowing for determination of affinity, KD, and interaction rate constants, kon and koff, was adopted. The increased physiological relevance of this method was confirmed, and the affinity data have better correlation with cell culture data. In addition, interactions between clinical inhibitors of HIV protease and enzyme variants indicate that increased dissociation rates (koff) are associated with the development of resistance.

Thermodynamic characterization of the interactions between HIV-1 protease and clinically relevant inhibitors revealed distinct energetic characteristics for inhibitors. The resolution of the energetics of association and dissociation identified an inhibitor with unique interaction characteristics and confirmed the validity of using this method for further characterization of molecular interactions.

This work resulted in the development of model systems for the analysis of kinetics, resistance and thermodynamic characteristics of protein-inhibitor interactions. The results give increased understanding of the biomolecular interactions and can be applied to drug discovery.

Place, publisher, year, edition, pages
Uppsala: Acta Universitatis Upsaliensis, 2003. 49 p.
Series
Comprehensive Summaries of Uppsala Dissertations from the Faculty of Science and Technology, ISSN 1104-232X ; 822
Keyword
Biochemistry, viral proteases, biomolecular interactions, kinetics, thermodynamics, biosensors, drug discovery, Biokemi
National Category
Biochemistry and Molecular Biology
Research subject
Biochemistry
Identifiers
urn:nbn:se:uu:diva-3342 (URN)91-554-5568-9 (ISBN)
Public defence
2003-04-25, lecture hall B42, Uppsala, 10:15 (English)
Opponent
Available from: 2003-04-01 Created: 2003-04-01 Last updated: 2017-05-04Bibliographically approved

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Danielson, U. Helena

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