title: Efficient search of chemical space: navigating from fragments to structurally diverse chemotypes.
abstract: We introduce a novel strategy to sample bioactive chemical space, which follows-up on hits from fragment campaigns without the need for a crystal structure. Our results strongly suggest that screening a few hundred or thousand fragments can substantially improve the selection of small-molecule screening subsets. By combining fragment-based screening with virtual fragment linking and HTS fingerprints, we have developed an effective strategy not only to expand from low-affinity hits to potent compounds but also to hop in chemical space to substantially novel chemotypes. In benchmark calculations, our approach accessed subsets of compounds that were substantially enriched in chemically diverse hit compounds for various activity classes. Overall, half of the hits in the screening collection were found by screening only 10% of the library. Furthermore, a prospective application led to the discovery of two structurally novel histone deacetylase 4 inhibitors.
authors.affiliation: Novartis Institutes for Biomedical Research Inc. , 250 Massachusetts Avenue, Cambridge, Massachusetts 02139, United States.
authors.forename: Anne Mai
authors.initials: AM
authors.lastname: Wassermann
authors.forename: Peter S
authors.initials: PS
authors.lastname: Kutchukian
authors.forename: Eugen
authors.initials: E
authors.lastname: Lounkine
authors.forename: Tiffany
authors.initials: T
authors.lastname: Luethi
authors.forename: Jacques
authors.initials: J
authors.lastname: Hamon
authors.forename: Michael T
authors.initials: MT
authors.lastname: Bocker
authors.forename: Hasnain A
authors.initials: HA
authors.lastname: Malik
authors.forename: Sandra W
authors.initials: SW
authors.lastname: Cowan-Jacob
authors.forename: Meir
authors.initials: M
authors.lastname: Glick
mesh_terms: D055808:Drug Discovery; D004791:Enzyme Inhibitors / Q000737:chemistry* / Q000494:pharmacology; D004798:Enzymes / Q000378:metabolism; D057166:High-Throughput Screening Assays; D008958:Models, Molecular; D015394:Molecular Structure; D054852:Small Molecule Libraries / Q000737:chemistry* / Q000494:pharmacology; D013329:Structure-Activity Relationship
chemical_list: D004791:Enzyme Inhibitors; D004798:Enzymes; D054852:Small Molecule Libraries