%0 Journal Article %1 Geitmann2006HIVRTInhibitorKinetics %A Geitmann, Matthis %A Unge, Torsten %A Danielson, U. Helena %D 2006 %J Journal of Medicinal Chemistry %K HIV-RT drug-discovery drug-kinetics drugs inhibition inhibitors kinetics %N 8 %P 2367-2374 %R 10.1021/jm0504048 %T Biosensor-Based Kinetic Characterization of the Interaction between HIV-1 Reverse Transcriptase and Non-nucleoside Inhibitors %U http://dx.doi.org/10.1021/jm0504048 %V 49 %X 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.

@article{Geitmann2006HIVRTInhibitorKinetics, 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. }, added-at = {2017-06-22T22:01:19.000+0200}, author = {Geitmann, Matthis and Unge, Torsten and Danielson, U. Helena}, biburl = {https://www.bibsonomy.org/bibtex/2eeda526d150c52edc06b8df8718eda65/salotz}, description = {Biosensor-Based Kinetic Characterization of the Interaction between HIV-1 Reverse Transcriptase and Non-nucleoside Inhibitors - Journal of Medicinal Chemistry (ACS Publications)}, doi = {10.1021/jm0504048}, eprint = {http://dx.doi.org/10.1021/jm0504048}, interhash = {f2fca16d93d96377ae426f3f34937819}, intrahash = {eeda526d150c52edc06b8df8718eda65}, journal = {Journal of Medicinal Chemistry}, keywords = {HIV-RT drug-discovery drug-kinetics drugs inhibition inhibitors kinetics}, note = {PMID: 16610780}, number = 8, pages = {2367-2374}, timestamp = {2017-06-22T22:01:19.000+0200}, title = {Biosensor-Based Kinetic Characterization of the Interaction between HIV-1 Reverse Transcriptase and Non-nucleoside Inhibitors}, url = {http://dx.doi.org/10.1021/jm0504048}, volume = 49, year = 2006 }