Journal
JOURNAL OF BIOMOLECULAR SCREENING
Volume 16, Issue 1, Pages 15-25Publisher
SAGE PUBLICATIONS INC
DOI: 10.1177/1087057110389038
Keywords
SPR biosensor; fragment library; fragment screening; interaction analysis; enzyme
Funding
- Swedish International Cooperation Agency (SIDA)
- VINNOVA (Swedish Governmental Agency for Innovation Systems)
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A new fragment library for lead discovery has been designed and experimentally validated for use in surface plasmon resonance (SPR) biosensor-based screening. The 930 compounds in the library were selected from 4.6 million commercially available compounds using a series of physicochemical and medicinal chemistry filters. They were screened against 3 prototypical drug targets: HIV-1 protease, thrombin and carbonic anhydrase, and a nontarget: human serum albumin. Compound solubility was not a problem under the conditions used for screening. The high sensitivity of the sensor surfaces allowed the detection of interactions for 35% to 97% of the fragments, depending on the target protein. None of the fragments was promiscuous (i.e., interacted with a stoichiometry >= 5: 1 with all 4 proteins), and only 2 compounds dissociated slowly from all 4 proteins. The use of several targets proved valuable since several compounds would have been disqualified from the library on the grounds of promiscuity if fewer target proteins had been used. The experimental procedure allowed an efficient evaluation and exploration of the new fragment library and confirmed that the new library is suitable for SPR biosensor-based screening. (Journal of Biomolecular Screening 2011:15-25)
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