title: Fast and Efficient Fragment-Based Lead Generation by Fully Automated Processing and Analysis of Ligand-Observed NMR Binding Data.
abstract: NMR binding assays are routinely applied in hit finding and validation during early stages of drug discovery, particularly for fragment-based lead generation. To this end, compound libraries are screened by ligand-observed NMR experiments such as STD, T1ρ, and CPMG to identify molecules interacting with a target. The analysis of a high number of complex spectra is performed largely manually and therefore represents a limiting step in hit generation campaigns. Here we report a novel integrated computational procedure that processes and analyzes ligand-observed proton and fluorine NMR binding data in a fully automated fashion. A performance evaluation comparing automated and manual analysis results on (19)F- and (1)H-detected data sets shows that the program delivers robust, high-confidence hit lists in a fraction of the time needed for manual analysis and greatly facilitates visual inspection of the associated NMR spectra. These features enable considerably higher throughput, the assessment of larger libraries, and shorter turn-around times.
authors.affiliation: Mestrelab Research S.L. , Feliciano Barrera 9B - Baixo, 15706 Santiago de Compostela, Spain.
authors.forename: Chen
authors.initials: C
authors.lastname: Peng
authors.affiliation: Novartis Institutes for BioMedical Research , 5300 Chiron Way, Emeryville, California 94608, United States.
authors.forename: Alexandra
authors.initials: A
authors.lastname: Frommlet
authors.affiliation: Mestrelab Research S.L. , Feliciano Barrera 9B - Baixo, 15706 Santiago de Compostela, Spain.
authors.forename: Manuel
authors.initials: M
authors.lastname: Perez
authors.affiliation: Mestrelab Research S.L. , Feliciano Barrera 9B - Baixo, 15706 Santiago de Compostela, Spain.
authors.forename: Carlos
authors.initials: C
authors.lastname: Cobas
authors.affiliation: Novartis Institutes for BioMedical Research , 5300 Chiron Way, Emeryville, California 94608, United States.
authors.forename: Anke
authors.initials: A
authors.lastname: Blechschmidt
authors.affiliation: Mestrelab Research S.L. , Feliciano Barrera 9B - Baixo, 15706 Santiago de Compostela, Spain.
authors.forename: Santiago
authors.initials: S
authors.lastname: Dominguez
authors.affiliation: Novartis Institutes for BioMedical Research , 5300 Chiron Way, Emeryville, California 94608, United States.
authors.forename: Andreas
authors.initials: A
authors.lastname: Lingel
mesh_terms: D062126:Databases, Chemical; D015195:Drug Design; D055808:Drug Discovery / Q000379:methods*; D005462:Fluorine Radioisotopes / Q000737:chemistry; D057166:High-Throughput Screening Assays / Q000379:methods*; D006801:Humans; D008024:Ligands; D009682:Magnetic Resonance Spectroscopy / Q000379:methods*; D011485:Protein Binding; D054852:Small Molecule Libraries / Q000737:chemistry*
chemical_list: D005462:Fluorine Radioisotopes; D008024:Ligands; D054852:Small Molecule Libraries