Data Deposition: Atomic co-ordinates and structure factors have been deposited with the Protein Data Bank (http://www.rcsb.org) for six structures listed in † (PDB codes 3KF1, 3KF0, 3KFN, 3KFP, 3KFR, and 3KFS).
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Fragment-Based Screen against HIV Protease
Article first published online: 19 JAN 2010
DOI: 10.1111/j.1747-0285.2009.00943.x
© 2010 John Wiley & Sons A/S
Additional Information
How to Cite
Perryman, A. L., Zhang, Q., Soutter, H. H., Rosenfeld, R., McRee, D. E., Olson, A. J., Elder, J. E. and David Stout, C. (2010), Fragment-Based Screen against HIV Protease. Chemical Biology & Drug Design, 75: 257–268. doi: 10.1111/j.1747-0285.2009.00943.x
Publication History
- Issue published online: 25 JAN 2010
- Article first published online: 19 JAN 2010
- Received 7 November 2009, revised 8 December 2009 and accepted for publication 8 December 2009
Keywords:
- allosteric inhibitor;
- crystal structure;
- fragment screen;
- HIV protease;
- multidrug resistance
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 Å 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 Gly16Gly17Gln18loop where the amide of Gly17is a specific hydrogen bond donor, and hydrophobic contacts occur with the side chains of Lys14and Leu63. Another fragment, indole-6-carboxylic acid, binds on the ‘outside/top of the flap’ via hydrophobic contacts with Trp42, Pro44, Met46, and Lys55, a hydrogen bond with Val56, and a salt-bridge with Arg57. 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.