title: Analysis of Iterative Screening with Stepwise Compound Selection Based on Novartis In-house HTS Data.
abstract: With increased automation and larger compound collections, the development of high-throughput screening (HTS) started replacing previous approaches in drug discovery from around the 1980s onward. However, even today it is not always appropriate, or even feasible, to screen large collections of compounds in a particular assay. Here, we present an efficient method for iterative screening of small subsets of compound libraries. With this method, the retrieval of active compounds is optimized using their structural information and biological activity fingerprints. We validated this approach retrospectively on 34 Novartis in-house HTS assays covering a wide range of assay biology, including cell proliferation, antibacterial activity, gene expression, and phosphorylation. This method was employed to retrieve subsets of compounds for screening, where selected hits from any given round of screening were used as starting points to select chemically and biologically similar compounds for the next iteration. By only screening ∼1% of the full screening collection (∼15 000 compounds), the method consistently retrieves diverse compounds belonging to the top 0.5% of the most active compounds for the HTS campaign. For most of the assays, over half of the compounds selected by the method were found to be among the 5% most active compounds of the corresponding full-deck HTS. In addition, the stringency of the iterative method can be modified depending on the number of compounds one can afford to screen, making it a flexible tool to discover active compounds efficiently.
authors.affiliation: Centre for Molecular Informatics, Department of Chemistry, University of Cambridge , Lensfield Road, CB2 1EW, Cambridge, United Kingdom.|Division of Medicinal Chemistry, Leiden Academic Centre for Drug Research, Leiden University , P.O. Box 9502, 2300 RA Leiden, The Netherlands.|Novartis Institutes for BioMedical Research, Novartis Pharma AG , Novartis Campus, 4056 Basel, Switzerland.
authors.forename: Shardul
authors.initials: S
authors.lastname: Paricharak
authors.affiliation: Division of Medicinal Chemistry, Leiden Academic Centre for Drug Research, Leiden University , P.O. Box 9502, 2300 RA Leiden, The Netherlands.
authors.forename: Adriaan P
authors.initials: AP
authors.lastname: IJzerman
authors.affiliation: Centre for Molecular Informatics, Department of Chemistry, University of Cambridge , Lensfield Road, CB2 1EW, Cambridge, United Kingdom.
authors.forename: Andreas
authors.initials: A
authors.lastname: Bender
authors.affiliation: Novartis Institutes for BioMedical Research, Novartis Pharma AG , Novartis Campus, 4056 Basel, Switzerland.
authors.forename: Florian
authors.initials: F
authors.lastname: Nigsch
mesh_terms: D000465:Algorithms; D000818:Animals; D004353:Drug Evaluation, Preclinical / Q000191:economics* / Q000379:methods*; D057166:High-Throughput Screening Assays / Q000191:economics / Q000379:methods; D006801:Humans; D047428:Protein Kinase Inhibitors / Q000737:chemistry / Q000494:pharmacology; D054852:Small Molecule Libraries / Q000737:chemistry / Q000494:pharmacology*; D013329:Structure-Activity Relationship
chemical_list: D047428:Protein Kinase Inhibitors; D054852:Small Molecule Libraries