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-nucleoside inhibitors in complex with HIV-1 reverse transcriptase to high-resolution limits of 2.7 Å (BM +21.1326) and 2.52 Å (BM +50.0934). We find that the binding modes of this series of inhibitors closely resemble 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 structures suggest modifications to the inhibitors that might improve resilience to drug-resistant mutant forms of reverse transcriptase. Comparison with earlier modeling studies reveals that the predicted overlap of thiazoloisoindolinones with TIBO was largely correct, while that with nevirapine was significantly different.