Crystallographic analysis of the binding modes of thiazoloisoindolinone non-nucleoside inhibitors to HIV-1 reverse transcriptase and comparison with modeling studies

We have determined the crystal structures of thiazoloisoindolinone non-nucl eoside inhibitors in complex with HIV-1 reverse transcriptase to high-resol ution limits of 2.7 Angstrom (BM +21.1326) and 2.52 Angstrom (BM +50.0934). We find that the binding modes of this series of inhibitors closely resemb le that of "two-ring'' non-nucleoside reverse transcriptase inhibitors. The structures allow rationalization of stereochemical requirements, structure -activity data, and drug resistance data. Comparisons with our previous str uctures suggest modifications to the inhibitors that might improve resilien ce to drug-resistant mutant forms of reverse transcriptase. Comparison with earlier modeling studies reveals that the predicted overlap of thiazoloiso indolinones with TIBO was largely correct, while that with nevirapine was s ignificantly different.