title: Virtual fragment screening: discovery of histamine H3 receptor ligands using ligand-based and protein-based molecular fingerprints.
abstract: Virtual fragment screening (VFS) is a promising new method that uses computer models to identify small, fragment-like biologically active molecules as useful starting points for fragment-based drug discovery (FBDD). Training sets of true active and inactive fragment-like molecules to construct and validate target customized VFS methods are however lacking. We have for the first time explored the possibilities and challenges of VFS using molecular fingerprints derived from a unique set of fragment affinity data for the histamine H(3) receptor (H(3)R), a pharmaceutically relevant G protein-coupled receptor (GPCR). Optimized FLAP (Fingerprints of Ligands and Proteins) models containing essential molecular interaction fields that discriminate known H(3)R binders from inactive molecules were successfully used for the identification of new H(3)R ligands. Prospective virtual screening of 156,090 molecules yielded a high hit rate of 62% (18 of the 29 tested) experimentally confirmed novel fragment-like H(3)R ligands that offer new potential starting points for the design of H(3)R targeting drugs. The first construction and application of customized FLAP models for the discovery of fragment-like biologically active molecules demonstrates that VFS is an efficient way to explore protein-fragment interaction space in silico.
authors.affiliation: Laboratory for Chemometrics and Chemoinformatics, Chemistry Department, University of Perugia, Via Elce di Sotto, 10, I-06123 Perugia, Italy.
authors.forename: Francesco
authors.initials: F
authors.lastname: Sirci
authors.forename: Enade P
authors.initials: EP
authors.lastname: Istyastono
authors.forename: Henry F
authors.initials: HF
authors.lastname: Vischer
authors.forename: Albert J
authors.initials: AJ
authors.lastname: Kooistra
authors.forename: Saskia
authors.initials: S
authors.lastname: Nijmeijer
authors.forename: Martien
authors.initials: M
authors.lastname: Kuijer
authors.forename: Maikel
authors.initials: M
authors.lastname: Wijtmans
authors.forename: Raimund
authors.initials: R
authors.lastname: Mannhold
authors.forename: Rob
authors.initials: R
authors.lastname: Leurs
authors.forename: Iwan J P
authors.initials: IJ
authors.lastname: de Esch
authors.forename: Chris
authors.initials: C
authors.lastname: de Graaf
mesh_terms: D019295:Computational Biology; D030562:Databases, Protein; D016002:Discriminant Analysis; D004353:Drug Evaluation, Preclinical / Q000379:methods*; D008024:Ligands; D062105:Molecular Docking Simulation; D011487:Protein Conformation; D018100:Receptors, Histamine H3 / Q000737:chemistry* / Q000378:metabolism*; D014584:User-Computer Interface
chemical_list: D008024:Ligands; D018100:Receptors, Histamine H3