title: Open PHACTS computational protocols forin silicotarget validation of cellular phenotypic screens: knowing the knowns.
abstract: Phenotypic screening is in a renaissance phase and is expected by many academic and industry leaders to accelerate the discovery of new drugs for new biology. Given that phenotypic screening is per definition target agnostic, the emphasis ofin silicoandin vitrofollow-up work is on the exploration of possible molecular mechanisms and efficacy targets underlying the biological processes interrogated by the phenotypic screening experiments. Herein, we present six exemplar computational protocols for the interpretation of cellular phenotypic screens based on the integration of compound, target, pathway, and disease data established by the IMI Open PHACTS project. The protocols annotate phenotypic hit lists and allow follow-up experiments and mechanistic conclusions. The annotations included are from ChEMBL, ChEBI, GO, WikiPathways and DisGeNET. Also provided are protocols which select from the IUPHAR/BPS Guide to PHARMACOLOGY interaction file selective compounds to probe potential targets and a correlation robot which systematically aims to identify an overlap of active compounds in both the phenotypic as well as any kinase assay. The protocols are applied to a phenotypic pre-lamin A/C splicing assay selected from the ChEMBL database to illustrate the process. The computational protocols make use of the Open PHACTS API and data and are built within the Pipeline Pilot and KNIME workflow tools.
authors: Department of Pharmaceutical Chemistry , University of Vienna , Pharmacoinformatics Research Group , Althanstraße 14 , 1090 Wien , Austria . Email: daniela.digles@univie.ac.at.
authors: D
authors: D
authors: Digles
authors: Department of Pharmaceutical Chemistry , University of Vienna , Pharmacoinformatics Research Group , Althanstraße 14 , 1090 Wien , Austria . Email: daniela.digles@univie.ac.at.
authors: B
authors: B
authors: Zdrazil
authors: Janssen Research & Development , Turnhoutseweg 30 , B-2340 Beerse , Belgium . Email: ejacoby@its.jnj.com.
authors: J-M
authors: JM
authors: Neefs
authors: Janssen Research & Development , Turnhoutseweg 30 , B-2340 Beerse , Belgium . Email: ejacoby@its.jnj.com.
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authors: Van Vlijmen
authors: Merck KGaA, Merck Serono R&D , Computational Chemistry , Frankfurter Straße 250 , 64293 Darmstadt , Germany.
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authors: Herhaus
authors: BIOVIA , a Dassault Systèmes brand , 334 Cambridge Science Park , Cambridge CB4 0WN , UK.
authors: A
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authors: Caracoti
authors: Grupo BioFarma-USEF , Departamento de Farmacología , Facultad de Farmacia , Campus Universitario Sur s/n , 15782 Santiago de Compostela , Spain.
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authors: Grupo BioFarma-USEF , Departamento de Farmacología , Facultad de Farmacia , Campus Universitario Sur s/n , 15782 Santiago de Compostela , Spain.
authors: B
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authors: Grupo BioFarma-USEF , Departamento de Farmacología , Facultad de Farmacia , Campus Universitario Sur s/n , 15782 Santiago de Compostela , Spain.
authors: M I
authors: MI
authors: Loza
authors: Research Programme on Biomedical Informatics (GRIB) , Hospital del Mar Medical Research Institute (IMIM) , Department of Experimental and Health Sciences , Universitat Pompeu Fabra , C/Dr Aiguader 88 , E-08003 Barcelona , Spain.
authors: N
authors: N
authors: Queralt-Rosinach
authors: Research Programme on Biomedical Informatics (GRIB) , Hospital del Mar Medical Research Institute (IMIM) , Department of Experimental and Health Sciences , Universitat Pompeu Fabra , C/Dr Aiguader 88 , E-08003 Barcelona , Spain.
authors: L I
authors: LI
authors: Furlong
authors: European Molecular Biology Laboratory , European Bioinformatics Institute (EMBL-EBI) , Wellcome Genome Campus , Hinxton , Cambridge CB10 1SD , UK.
authors: A
authors: A
authors: Gaulton
authors: GlaxoSmithKline , Medicines Research Centre , Stevenage SG1 2NY , UK.
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authors: Bartek
authors: GlaxoSmithKline , Medicines Research Centre , Stevenage SG1 2NY , UK.
authors: S
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authors: Senger
authors: Swiss Institute of Bioinformatics , CALIPHO Group , CMU Rue Michel-Servet 1 , 1211 Geneva 4 , Switzerland ; Nestlé Institute of Health Sciences SA , EPFL Innovation Park, Bâtiment H , 1015 Lausanne , Switzerland.
authors: C
authors: C
authors: Chichester
authors: Chemistry Innovation Centre , Discovery Sciences , AstraZeneca R&D Gothenburg , SE-431 83 Mölndal , Sweden.
authors: O
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authors: Engkvist
authors: Department of Bioinformatics - BiGCaT , P.O. Box 616 , UNS50 Box19 , NL-6200MD Maastricht , The Netherlands.
authors: C T
authors: CT
authors: Evelo
authors: Open Innovation Drug Discovery , Discovery Chemistry Eli Lilly and Company , Lilly Corporate Center , DC 1920 , Indianapolis , IN 46285 , USA.
authors: N I
authors: NI
authors: Franklin
authors: Eli Lilly and Company Ltd. , Lilly Research Centre , Erl Wood Manor, Sunninghill Road , Windlesham , Surrey GU20 6PH , England , UK.
authors: D
authors: D
authors: Marren
authors: Department of Pharmaceutical Chemistry , University of Vienna , Pharmacoinformatics Research Group , Althanstraße 14 , 1090 Wien , Austria . Email: daniela.digles@univie.ac.at.
authors: G F
authors: GF
authors: Ecker
authors: Janssen Research & Development , Turnhoutseweg 30 , B-2340 Beerse , Belgium . Email: ejacoby@its.jnj.com.
authors: E
authors: E
authors: Jacoby