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Polypharmacological in Silico Bioactivity Profiling and Experimental Validation Uncovers Sedative-Hypnotic Effects of Approved and Experimental Drugs in Rat

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cam.issuedOnline2017-04-17
dc.contributor.authorDrakakis, G
dc.contributor.authorWafford, KA
dc.contributor.authorBrewerton, SC
dc.contributor.authorBodkin, MJ
dc.contributor.authorEvans, DA
dc.contributor.authorBender, A
dc.contributor.orcidDrakakis, Georgios [0000-0002-6635-9273]
dc.contributor.orcidBender, Andreas [0000-0002-6683-7546]
dc.date.accessioned2017-08-23T15:55:59Z
dc.date.available2017-08-23T15:55:59Z
dc.date.issued2017-06-16
dc.description.abstractIn this work, we describe the computational ("in silico") mode-of-action analysis of CNS-active drugs, which is taking both multiple simultaneous hypotheses as well as sets of protein targets for each mode-of-action into account, and which was followed by successful prospective in vitro and in vivo validation. Using sleep-related phenotypic readouts describing both efficacy and side effects for 491 compounds tested in rat, we defined an "optimal" (desirable) sleeping pattern. Compounds were subjected to in silico target prediction (which was experimentally confirmed for 21 out of 28 cases), followed by the utilization of decision trees for deriving polypharmacological bioactivity profiles. We demonstrated that predicted bioactivities improved classification performance compared to using only structural information. Moreover, DrugBank molecules were processed via the same pipeline, and compounds in many cases not annotated as sedative-hypnotic (alcaftadine, benzatropine, palonosetron, ecopipam, cyproheptadine, sertindole, and clopenthixol) were prospectively validated in vivo. Alcaftadine, ecopipam cyproheptadine, and clopenthixol were found to promote sleep as predicted, benzatropine showed only a small increase in NREM sleep, whereas sertindole promoted wakefulness. To our knowledge, the sedative-hypnotic effects of alcaftadine and ecopipam have not been previously discussed in the literature. The method described extends previous single-target, single-mode-of-action models and is applicable across disease areas.
dc.description.sponsorshipThis research was supported by Unilever (A.B.), the EPSRC (G.D.), and Eli Lilly (G.D.). A.B. thanks the ERC for an ERC Starting Grant.
dc.identifier.doi10.17863/CAM.12884
dc.identifier.eissn1554-8937
dc.identifier.issn1554-8929
dc.identifier.urihttps://www.repository.cam.ac.uk/handle/1810/266813
dc.languageeng
dc.language.isoeng
dc.publisherAmerican Chemical Society
dc.publisher.urlhttp://dx.doi.org/10.1021/acschembio.7b00209
dc.subjectAnimals
dc.subjectBenzazepines
dc.subjectBiomedical Research
dc.subjectComputer Simulation
dc.subjectHypnotics and Sedatives
dc.subjectImidazoles
dc.subjectPolypharmacology
dc.subjectRats
dc.titlePolypharmacological in Silico Bioactivity Profiling and Experimental Validation Uncovers Sedative-Hypnotic Effects of Approved and Experimental Drugs in Rat
dc.typeArticle
dcterms.dateAccepted2017-04-17
prism.endingPage1602
prism.issueIdentifier6
prism.publicationDate2017
prism.publicationNameACS Chemical Biology
prism.startingPage1593
prism.volume12
rioxxterms.licenseref.startdate2017-06-16
rioxxterms.licenseref.urihttp://www.rioxx.net/licenses/all-rights-reserved
rioxxterms.typeJournal Article/Review
rioxxterms.versionAM
rioxxterms.versionofrecord10.1021/acschembio.7b00209

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