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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 A (BM +21.1326) and 2. 52 A (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.

Original publication

DOI

10.1021/jm990275t

Type

Journal article

Journal

Journal of medicinal chemistry

Publication Date

09/1999

Volume

42

Pages

3845 - 3851

Addresses

Laboratory of Molecular Biophysics, Rex Richards Building, South Parks Road, Oxford OX1 3QU, U.K..

Keywords

Thiazoles, Indoles, Reverse Transcriptase Inhibitors, Crystallography, X-Ray, Protein Conformation, Protein Binding, Structure-Activity Relationship, Models, Chemical, Models, Molecular, HIV Reverse Transcriptase