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Characterization of a Set of HIV-1 Protease Inhibitors Using Binding Kinetics Data from a Biosensor-Based Screen

Biacore AB, Uppsala, Sweden

Per-Olof Markgren

Department of Biochemistry, Uppsala University, Uppsala, Sweden

Wesley Schaal

Department of Organic Pharmaceutical Chemistry, Uppsala University, Uppsala, Sweden

Anders Karlén

Department of Organic Pharmaceutical Chemistry, Uppsala University, Uppsala, Sweden

Bjorn Classon

Medivir AB, Huddinge, Sweden

Lotta Vrang

Medivir AB, Huddinge, Sweden

Bertil Samuelsson

IFM Kemi, Linkbping University, Linkdping, Sweden

Anders Hallberg

Department of Organic Pharmaceutical Chemistry, Uppsala University, Uppsala, Sweden

U. Helena Danielson

Department of Biochemistry, Uppsala University, Uppsala, Sweden

The interaction between 290 structurally diverse human immunodeficiency virus type 1 (HIV-1) protease inhibitors and the immobilized enzyme was analyzed with an optical biosensor. Although only a single concentration of inhibitor was used, information about the kinetics of the interaction could be obtained by extracting binding signals at discrete time points. The statistical correlation between the biosensor binding data, inhibition of enzyme activity (K;), and viral replication (EC₅₀) revealed that the association and dissociation rates for the interaction could be resolved and that they were characteristic for the compounds. The most potent inhibitors, with respect to K; and EC5₀ values, including the clinically used drugs, all exhibited fast association and slow dissociation rates. Selective or partially selective binders for HIV-1 protease could be distinguished from compounds that showed a general protein-binding tendency by using three reference target proteins. This biosensor-based direct binding assay revealed a capacity to efficiently provide high-resolution information on the interaction kinetics and specificity of the interaction of a set of compounds with several targets simultaneously.

Journal of Biomolecular Screening, Vol. 5, No. 5, 353-359 (2000)
DOI: 10.1177/108705710000500507


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