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dc.contributor.authorJokinen, Elmeri M.
dc.contributor.authorPostila, Pekka A.
dc.contributor.authorAhinko, Mira
dc.contributor.authorNiinivehmas, Sanna
dc.contributor.authorPentikäinen, Olli T.
dc.date.accessioned2019-08-23T05:41:42Z
dc.date.available2019-08-23T05:41:42Z
dc.date.issued2019
dc.identifier.citationJokinen, E. M., Postila, P. A., Ahinko, M., Niinivehmas, S., & Pentikäinen, O. T. (2019). Fragment‐ and Negative Image‐Based Screening of Phosphodiesterase 10A Inhibitors. <i>Chemical Biology and Drug Design</i>, <i>94</i>(4), 1799-1812. <a href="https://doi.org/10.1111/cbdd.13584" target="_blank">https://doi.org/10.1111/cbdd.13584</a>
dc.identifier.otherCONVID_31382011
dc.identifier.urihttps://jyx.jyu.fi/handle/123456789/65279
dc.description.abstractA novel virtual screening methodology called fragment‐ and negative image‐based (F‐NiB) screening is introduced and tested experimentally using phosphodiesterase 10A (PDE10A) as a case study. Potent PDE10A‐specific small‐molecule inhibitors are actively sought after for their antipsychotic and neuroprotective effects. The F‐NiB combines features from both fragment‐based drug discovery and negative image‐based (NIB) screening methodologies to facilitate rational drug discovery. The selected structural parts of protein‐bound ligand(s) are seamlessly combined with the negative image of the target's ligand‐binding cavity. This cavity‐ and fragment‐based hybrid model, namely its shape and electrostatics, is used directly in the rigid docking of ab initio generated ligand 3D conformers. In total, 14 compounds were acquired using the F‐NiB methodology, 3D quantitative structure‐activity relationship modeling and pharmacophore modeling. Three of the small‐molecules inhibited PDE10A at ~27 μM to ~67 μM range in a radiometric assay. In a larger context, the study shows that the F‐NiB provides a flexible way to incorporate small‐molecule fragments into the drug discovery.en
dc.format.mimetypeapplication/pdf
dc.languageeng
dc.language.isoeng
dc.publisherWiley-Blackwell Publishing, Inc.
dc.relation.ispartofseriesChemical Biology and Drug Design
dc.rightsIn Copyright
dc.subject.otherskitsofrenia
dc.subject.otherParkinsonin tauti
dc.subject.otherHuntingtonin tauti
dc.subject.otherlääkkeet
dc.subject.otherphosphodiesterase 10A (PDE10A)
dc.subject.otherschizophrenia
dc.subject.otherParkinson’s disease
dc.subject.otherHuntington’s disease
dc.subject.othernegative image based (NIB)
dc.subject.otherfragment
dc.subject.othernegative image based (FNiB) screening
dc.subject.othervirtual screening
dc.subject.otherstructure-based virtual screening
dc.subject.otherradiometric activity assay
dc.subject.otherfragment-based drug discovery
dc.titleFragment‐ and Negative Image‐Based Screening of Phosphodiesterase 10A Inhibitors
dc.typearticle
dc.identifier.urnURN:NBN:fi:jyu-201908233880
dc.contributor.laitosBio- ja ympäristötieteiden laitosfi
dc.contributor.laitosMatemaattis-luonnontieteellinen tiedekuntafi
dc.contributor.laitosDepartment of Biological and Environmental Scienceen
dc.contributor.laitosFaculty of Mathematics and Scienceen
dc.contributor.oppiaineSolu- ja molekyylibiologiafi
dc.contributor.oppiaineNanoscience Centerfi
dc.contributor.oppiaineCell and Molecular Biologyen
dc.contributor.oppiaineNanoscience Centeren
dc.type.urihttp://purl.org/eprint/type/JournalArticle
dc.description.reviewstatuspeerReviewed
dc.format.pagerange1799-1812
dc.relation.issn1747-0277
dc.relation.numberinseries4
dc.relation.volume94
dc.type.versionacceptedVersion
dc.rights.copyright© 2019 John Wiley & Sons A/S
dc.rights.accesslevelopenAccessfi
dc.subject.ysolääkkeet
dc.subject.ysoHuntingtonin tauti
dc.subject.ysoParkinsonin tauti
dc.subject.ysoseulonta
dc.subject.ysoskitsofrenia
dc.format.contentfulltext
jyx.subject.urihttp://www.yso.fi/onto/yso/p1077
jyx.subject.urihttp://www.yso.fi/onto/yso/p18497
jyx.subject.urihttp://www.yso.fi/onto/yso/p294
jyx.subject.urihttp://www.yso.fi/onto/yso/p11811
jyx.subject.urihttp://www.yso.fi/onto/yso/p9659
dc.rights.urlhttp://rightsstatements.org/page/InC/1.0/?language=en
dc.relation.doi10.1111/cbdd.13584
jyx.fundinginformationThe project was funded by the Jenny and Antti Wihuri Foundation (MA), the Emil Aaltonen Foundation (MA), the Finnish Cultural Foundation, Varsinais‐Suomi Regional fund (EMJ; 85182232), and the Academy of Finland (SN; 315492). CSC, The Finnish IT Centre for Science, is acknowledged for generous computational grants (O.T.P. projects jyy2516, jyy2585, and jyy2586).


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