Comprehensive mechanistic analysis of hits from high-throughput and docking screens against beta-lactamase.

@article{Babaoglu2008ComprehensiveMA,
  title={Comprehensive mechanistic analysis of hits from high-throughput and docking screens against beta-lactamase.},
  author={Kerim Babaoglu and Anton Simeonov and John J. Irwin and Michael E. Nelson and Brian Y Feng and Craig J. Thomas and Laura Cancian and Maria Paola Costi and David A. Maltby and Ajit Jadhav and James Inglese and Christopher P. Austin and Brian K. Shoichet},
  journal={Journal of medicinal chemistry},
  year={2008},
  volume={51 8},
  pages={
          2502-11
        }
}
High-throughput screening (HTS) is widely used in drug discovery. Especially for screens of unbiased libraries, false positives can dominate "hit lists"; their origins are much debated. Here we determine the mechanism of every active hit from a screen of 70,563 unbiased molecules against beta-lactamase using quantitative HTS (qHTS). Of the 1,274 initial inhibitors, 95% were detergent-sensitive and were classified as aggregators. Among the 70 remaining were 25 potent, covalent-acting beta… 

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References

SHOWING 1-10 OF 50 REFERENCES
A high-throughput screen for aggregation-based inhibition in a large compound library.
TLDR
Three key results emerge from this study: first, detergent-dependent identification of aggregate- based inhibition is feasible on the large scale, second, 95% of the actives obtained in this screen are aggregate-based inhibitors, and third, aggregate-Based inhibition is correlated with steep dose-response curves, although not absolutely.
High-throughput assays for promiscuous inhibitors
TLDR
Two rapid assays for detecting promiscuous aggregates that were used to test two preliminary computational models of this phenomenon and as benchmarks to develop new models are reported.
A common mechanism underlying promiscuous inhibitors from virtual and high-throughput screening.
TLDR
High-throughput and virtual screening is widely used to discover novel leads for drug design, and aggregate formation appears to explain the activity of many nonspecific inhibitors and may account for theActivity of many promiscuous screening hits.
Quantitative high-throughput screening: a titration-based approach that efficiently identifies biological activities in large chemical libraries.
TLDR
The feasibility of qHTS for accurately profiling every compound in large chemical libraries (>10(5) compounds) is demonstrated, thereby providing a platform for chemical genomics and accelerating the identification of leads for drug discovery.
Structure-based discovery of a novel, noncovalent inhibitor of AmpC beta-lactamase.
TLDR
The structure of the enzyme-inhibitor complex presents an opportunity to improve binding affinity in a novel series of inhibitors discovered by structure-based methods.
Deconstructing fragment-based inhibitor discovery
Fragment-based screens test multiple low–molecular weight molecules for binding to a target1,2,3,4. Fragments often bind with low affinities but typically have better ligand efficiencies
Development of a virtual screening method for identification of "frequent hitters" in compound libraries.
TLDR
A computer-based method was developed for rapid and automatic identification of potential "frequent hitters" that will be a valuable tool for the prioritization of compounds from large databases, for compound purchase and biological testing, and for building new virtual libraries.
A guide to drug discovery: Designing screens: how to make your hits a hit
TLDR
A recent trend in high-throughput screening has been to place less emphasis on the number of data points that can be produced, and to focus instead on the quality of the data obtained.
...
...