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A Chemoinformatics Analysis of Hit Lists Obtained from High-Throughput Affinity-Selection Screening

Novartis Institutes for BioMedical Research, Basel, Switzerland

Hartmut Zehender

Novartis Institutes for BioMedical Research, Basel, Switzerland

Kamal Azzaoui

Novartis Institutes for BioMedical Research, Basel, Switzerland

Ansgar Schuffenhauer

Novartis Institutes for BioMedical Research, Basel, Switzerland

Lorenz M. Mayr

Novartis Institutes for BioMedical Research, Basel, Switzerland

Edgar Jacoby

Novartis Institutes for BioMedical Research, Basel, Switzerland

The high-throughput affinity-selection screening platform SpeedScreen was recently reported by the Novartis Institutes for BioMedical Research as a homogeneous, label-free screening technology with mass-spectrometry readout. SpeedScreen relies on the screening of compound mixtures with various target proteins and uses fast size-exclusion chromatography to separate target-bound from unbound substances. After disintegration of the target-binder complex, the binder molecules are identified by their molecular masses using liquid chromatography/mass spectrometry. The authors report an analysis of the molecular properties of hits obtained with SpeedScreen on 26 targets screened within the past few years at Novartis using this technology. Affinity-based SpeedScreen is a robust high-throughput screening technology that does not accumulate frequent hitters or potential covalent binders. The hits are representative of the most commonly identified scaffold classes observed for known drugs. Validated SpeedScreen hits tend to be enriched on more lipophilic and larger-molecular-weight compounds compared to the whole library. The potential for a reduced SpeedScreen screening set to be used in case only limited protein quantities are available is evaluated. Such a reduced compound set should also maximize the coverage of the high-performing regions of the chemical property and class spaces; chemoinformatics methods including genetic algorithms and divisive K-means clustering are used for this aim.

Key Words: affinity-based high-throughput screening • SpeedScreen • chemoinformatics • chemoinformatics • scaffolds • genetic algorithms • subset selection • diversity

This version was published on March 1, 2006

Journal of Biomolecular Screening, Vol. 11, No. 2, 123-130 (2006)
DOI: 10.1177/1087057105283579


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