期刊
CHEMICAL BIOLOGY & DRUG DESIGN
卷 75, 期 3, 页码 257-268出版社
WILEY
DOI: 10.1111/j.1747-0285.2009.00943.x
关键词
allosteric inhibitor; crystal structure; fragment screen; HIV protease; multidrug resistance
资金
- NIH [P01 GM083658-01]
- U.S. Department of Energy, Office of Basic Energy Sciences
- Department of Energy, Office of Biological and Environmental Research
- National Institutes of Health
- National Center for Research Resources
- Biomedical Technology Program
- National Institute of General Medical Sciences
We have employed a fragment-based screen against wild-type (NL4-3) HIV protease (PR) using the Active Sight fragment library and X-ray crystallography. The experiments reveal two new binding sites for small molecules. PR was co-crystallized with fragments, or crystals were soaked in fragment solutions, using five crystal forms, and 378 data sets were collected to 2.3-1.3 angstrom resolution. Fragment binding induces a distinct conformation and specific crystal form of TL-3 inhibited PR during co-crystallization. One fragment, 2-methylcyclohexanol, binds in the 'exo site' adjacent to the Gly(16)Gly(17)Gln(18)loop where the amide of Gly(17) is a specific hydrogen bond donor, and hydrophobic contacts occur with the side chains of Lys(14) and Leu(63). Another fragment, indole-6-carboxylic acid, binds on the 'outside/top of the flap' via hydrophobic contacts with Trp(42), Pro(44), Met(46), and Lys(55), a hydrogen bond with Val(56), and a salt-bridge with Arg(57) . 2-acetyl-benzothiophene also binds at this site. This study is the first fragment-based crystallographic screen against HIV PR, and the first time that fragments were screened against an inhibitor-bound drug target to search for compounds that both bind to novel sites and stabilize the inhibited conformation of the target.
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