Biosensor-based kinetic characterization of the interaction between HIV-1 reverse transcriptase and non-nucleoside inhibitors
2006 (English)In: Journal of Medicinal Chemistry, ISSN 0022-2623, Vol. 49, no 8, 2367-74 p.Article in journal (Refereed) Published
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.
Place, publisher, year, edition, pages
2006. Vol. 49, no 8, 2367-74 p.
Binding Sites, Biosensing Techniques/*methods, Delavirdine/chemistry/pharmacology, Enzyme Activation/drug effects, HIV-1 Reverse Transcriptase/*antagonists & inhibitors/chemistry, Kinetics, Molecular Structure, Nevirapine/chemistry/pharmacology, Oxazines/chemistry/pharmacology, Protein Conformation, Pyridines/chemistry/pharmacology, Reverse Transcriptase Inhibitors/chemistry/*pharmacology, Structure-Activity Relationship, Time Factors, Urea/analogs & derivatives/chemistry/pharmacology
Biochemistry and Molecular Biology
IdentifiersURN: urn:nbn:se:uu:diva-18243DOI: 10.1021/jm0504048PubMedID: 16610780OAI: oai:DiVA.org:uu-18243DiVA: diva2:46015