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Prog Biophys Mol Biol. 2014 Nov-Dec;116(2-3):92-100. doi: 10.1016/j.pbiomolbio.2014.08.004. Epub 2014 Aug 10.

Advantages of crystallographic fragment screening: functional and mechanistic insights from a powerful platform for efficient drug discovery.

Author information

1
Center for Advanced Biotechnology and Medicine, Department of Chemistry and Chemical Biology, Rutgers University, Piscataway, NJ, USA.
2
Center for Advanced Biotechnology and Medicine, Department of Chemistry and Chemical Biology, Rutgers University, Piscataway, NJ, USA. Electronic address: arnold@cabm.rutgers.edu.

Abstract

X-ray crystallography has been an under-appreciated screening tool for fragment-based drug discovery due to the perception of low throughput and technical difficulty. Investigators in industry and academia have overcome these challenges by taking advantage of key factors that contribute to a successful crystallographic screening campaign. Efficient cocktail design and soaking methodologies have evolved to maximize throughput while minimizing false positives/negatives. In addition, technical improvements at synchrotron beamlines have dramatically increased data collection rates thus enabling screening on a timescale comparable to other techniques. The combination of available resources and efficient experimental design has resulted in many successful crystallographic screening campaigns. The three-dimensional crystal structure of the bound fragment complexed to its target, a direct result of the screening effort, enables structure-based drug design while revealing insights regarding protein dynamics and function not readily obtained through other experimental approaches. Furthermore, this "chemical interrogation" of the target protein crystals can lead to the identification of useful reagents for improving diffraction resolution or compound solubility.

KEYWORDS:

Fragment screening; HIV; Influenza; X-ray crystallography

PMID:
25117499
PMCID:
PMC4501029
DOI:
10.1016/j.pbiomolbio.2014.08.004
[Indexed for MEDLINE]
Free PMC Article

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