Biosensor-based Kinetic Characterization of the Interaction Between Hiv-1 Reverse Transcriptase and Non-nucleoside Inhibitors.
From: Department of Biochemistry and Organic Chemistry, Box 576, Uppsala University, SE-751 23 Uppsala, Sweden.
Journal of medicinal chemistry
- Publish Date: Apr 2006
- ISSN: 0022-2623
- Volume: 49
- Issue: 8
- Pages: 2367-74
- Medium: Print
- Language: English
- Citation (JAMA): Geitmann Matthis, Unge Torsten, Danielson U Helena, et al. Biosensor-based Kinetic Characterization of the Interaction Between Hiv-1 Reverse Transcriptase and Non-nucleoside Inhibitors.. J. Med. Chem. Apr 2006;49:2367-74
Abstract
Details of the interaction between HIV-1 reverse transcriptase and non-nucleoside inhibitors (NNRTIs) have been elucidated using a biosensor-based approach. This initial study was performed with HIV-1 reverse transcriptase mutant K103N, the phenethylthioazolylthiourea compound (PETT) MIV-150, and the three NNRTIs licensed for clinical use: nevirapine, delavirdine, and efavirenz. Mathematical evaluation of the experimental data with several interaction models revealed that the four inhibitors interacted with HIV-1 RT with varying degrees of complexity. The simplest adequate model accounted for two different conformations of the free enzyme, of which only one can bind the inhibitor, consistent with a previously hypothesized population-shift model including a preformation of the NNRTI binding site. In addition, a heterogeneous binding was observed for delavirdine, efavirenz, and MIV-150, indicating that two noncompetitive and kinetically distinct enzyme-inhibitor complexes could be formed. Furthermore, for these compounds, there were indications for ligand-induced conformational changes.
Mesh Headings (Keywords): Benzoxazines, Binding Sites, Biosensing Techniques, Delavirdine, Enzyme Activation, HIV Reverse Transcriptase, Kinetics, Molecular Structure, Nevirapine, Oxazines, Protein Conformation, Pyridines, Reverse Transcriptase Inhibitors, Structure-Activity Relationship, Time Factors, Urea
Check for Full Text / PubMed Unique Identifier (PMID): 16610780
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