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Updated: Jun 10, 2026
05:46
Rapid Screening of HIV Reverse Transcriptase and Integrase Inhibitors
Published on: April 9, 2014
Fragment-based screen against HIV protease
Alexander L Perryman1, Qing Zhang, Holly H Soutter
1Department of Molecular Biology, The Scripps Research Institute, 10550 N. Torrey Pines Rd., La Jolla, CA 92037, USA.
Chemical Biology & Drug Design
|July 28, 2010
Summary
This study used fragment-based screening and X-ray crystallography to discover two new binding sites on HIV protease. These findings identify novel targets for developing new antiviral therapies.
Area of Science:
- Structural Biology
- Drug Discovery
- Virology
Background:
- HIV protease (PR) is a critical target for antiretroviral therapy.
- Existing drugs target the active site, necessitating new strategies to overcome resistance.
Purpose of the Study:
- To identify novel binding sites on HIV protease using fragment-based screening.
- To characterize fragment binding and its effect on HIV protease conformation.
- To explore fragment binding to inhibitor-bound HIV protease.
Main Methods:
- Fragment-based screening using the Active Sight library.
- X-ray crystallography with multiple crystal forms.
- Data collection and analysis to 1.3 Å resolution.
Main Results:
- Two novel small-molecule binding sites on HIV protease were identified.
- Fragment binding induced distinct conformations and crystal forms.
- Specific fragments, 2-methylcyclohexanol and indole-6-carboxylic acid, were characterized at these sites.
Conclusions:
- This is the first fragment-based crystallographic screen against HIV protease.
- The study demonstrates a novel approach by screening fragments against an inhibitor-bound target.
- Findings provide a foundation for designing new HIV protease inhibitors targeting novel sites.
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