title: A Prospective Virtual Screening Study: Enriching Hit Rates and Designing Focus Libraries To Find Inhibitors of PI3Kδ and PI3Kγ.
abstract: Here, we report a high-throughput virtual screening (HTVS) study using phosphoinositide 3-kinase (both PI3Kγ and PI3Kδ). Our initial HTVS results of the Janssen corporate database identified small focused libraries with hit rates at 50% inhibition showing a 50-fold increase over those from a HTS (high-throughput screen). Further, applying constraints based on "chemically intuitive" hydrogen bonds and/or positional requirements resulted in a substantial improvement in the hit rates (versus no constraints) and reduced docking time. While we find that docking scoring functions are not capable of providing a reliable relative ranking of a set of compounds, a prioritization of groups of compounds (e.g., low, medium, and high) does emerge, which allows for the chemistry efforts to be quickly focused on the most viable candidates. Thus, this illustrates that it is not always necessary to have a high correlation between a computational score and the experimental data to impact the drug discovery process.
authors.affiliation: Discovery Sciences and ‡Immunology, Janssen Research & Development , San Diego, California 92121, United States.
authors.forename: Kelly L
authors.initials: KL
authors.lastname: Damm-Ganamet
authors.affiliation: Discovery Sciences and ‡Immunology, Janssen Research & Development , San Diego, California 92121, United States.
authors.forename: Scott D
authors.initials: SD
authors.lastname: Bembenek
authors.affiliation: Discovery Sciences and ‡Immunology, Janssen Research & Development , San Diego, California 92121, United States.
authors.forename: Jennifer W
authors.initials: JW
authors.lastname: Venable
authors.affiliation: Discovery Sciences and ‡Immunology, Janssen Research & Development , San Diego, California 92121, United States.
authors.forename: Glenda G
authors.initials: GG
authors.lastname: Castro
authors.affiliation: Discovery Sciences and ‡Immunology, Janssen Research & Development , San Diego, California 92121, United States.
authors.forename: Lieve
authors.initials: L
authors.lastname: Mangelschots
authors.affiliation: Discovery Sciences and ‡Immunology, Janssen Research & Development , San Diego, California 92121, United States.
authors.forename: Daniëlle C G
authors.initials: DC
authors.lastname: Peeters
authors.affiliation: Discovery Sciences and ‡Immunology, Janssen Research & Development , San Diego, California 92121, United States.
authors.forename: Heather M
authors.initials: HM
authors.lastname: Mcallister
authors.affiliation: Discovery Sciences and ‡Immunology, Janssen Research & Development , San Diego, California 92121, United States.
authors.forename: James P
authors.initials: JP
authors.lastname: Edwards
authors.affiliation: Discovery Sciences and ‡Immunology, Janssen Research & Development , San Diego, California 92121, United States.
authors.forename: Daniel
authors.initials: D
authors.lastname: Disepio
authors.affiliation: Discovery Sciences and ‡Immunology, Janssen Research & Development , San Diego, California 92121, United States.
authors.forename: Taraneh
authors.initials: T
authors.lastname: Mirzadegan
mesh_terms: D015195:Drug Design; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D057166:High-Throughput Screening Assays; D007527:Isoenzymes / Q000037:antagonists & inhibitors*; D062105:Molecular Docking Simulation; D000081082:Phosphoinositide-3 Kinase Inhibitors; D011446:Prospective Studies
chemical_list: D004791:Enzyme Inhibitors; D007527:Isoenzymes; D000081082:Phosphoinositide-3 Kinase Inhibitors