Journal
JOURNAL OF MEDICINAL CHEMISTRY
Volume 54, Issue 8, Pages 2727-2737Publisher
AMER CHEMICAL SOC
DOI: 10.1021/jm101536x
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Funding
- U.S. National Institutes of Health (NIH) [AI 27690, AI 087201]
- KU Leuven [GOA 10/014]
- Spanish MICINN [SAF2009-13914-C02]
- Comunidad de Madrid [S-BIO-0214-2006]
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tert-Butyldimethylsilyl-spiroaminooxathioledioxide (TSAO) compounds have an embedded thymidine-analogue backbone; however, TSAO compounds invoke non-nucleoside RT inhibitor (NNRTI) resistance mutations. Our crystal structure of RT:7 (TSAO-T) complex shows that 7 binds inside the NNRTI binding pocket, assuming a dragon shape, and interacts extensively with almost all the pocket residues. The structure also explains the structure activity relationships and resistance data for TSAO compounds. The binding of 7 causes hyper-expansion of the pocket and significant rearrangement of RT subdomains. This nonoptimal complex formation is apparently responsible (1) for the lower stability of a RT (p66/p51) dimer and (2) for the lower potency of 7 despite of its extensive interactions with RT. However, the HIV-1 RT:7 structure reveals novel design features such as (1). interactions with the conserved Tyr183 from the YMDD-motif and (2) a possible way for an NNRTI to reach the polymerase active site that may be exploited in designing new NNRTI.
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