Rigorous computational study reveals what docking overlooks : Double trouble from membrane association in protein kinase C modulators

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dc.contributor.author Lautala, Saara
dc.contributor.author Provenzani, Riccardo
dc.contributor.author Koivuniemi, Artturi
dc.contributor.author Kulig, Waldemar
dc.contributor.author Talman, Virpi
dc.contributor.author Rog, Tomasz
dc.contributor.author Tuominen, Raimo K.
dc.contributor.author Yli-Kauhaluoma, Jari
dc.contributor.author Bunker, Alex Edwin
dc.date.accessioned 2021-09-10T22:29:45Z
dc.date.available 2021-12-18T03:45:24Z
dc.date.issued 2020-11-23
dc.identifier.citation Lautala , S , Provenzani , R , Koivuniemi , A , Kulig , W , Talman , V , Rog , T , Tuominen , R K , Yli-Kauhaluoma , J & Bunker , A E 2020 , ' Rigorous computational study reveals what docking overlooks : Double trouble from membrane association in protein kinase C modulators ' , Journal of Chemical Information and Modeling , vol. 60 , no. 11 , pp. 5624-5633 . https://doi.org/10.1021/acs.jcim.0c00624
dc.identifier.other PURE: 135554909
dc.identifier.other PURE UUID: ccf6185a-9296-411a-b259-6ca39cbe63e1
dc.identifier.other ORCID: /0000-0002-1236-9513/work/84701338
dc.identifier.other ORCID: /0000-0002-2702-6505/work/84702125
dc.identifier.other ORCID: /0000-0002-6780-1924/work/84704247
dc.identifier.other ORCID: /0000-0001-7568-0029/work/84704680
dc.identifier.other ORCID: /0000-0002-3979-7809/work/84706574
dc.identifier.other ORCID: /0000-0003-0370-7653/work/84702851
dc.identifier.other WOS: 000595488600029
dc.identifier.uri http://hdl.handle.net/10138/334259
dc.description.abstract Increasing protein kinase C (PKC) activity is of potential therapeutic value. Its activation involves an interaction between the C1 domain and diacylglycerol (DAG) at intracellular membrane surfaces; DAG mimetics hold promise as new drugs. We previously developed the isophthalate derivative HMI-1a3, an effective but highly lipophilic (clogP = 6.46) DAG mimetic. Although a less lipophilic pyrimidine analog, PYR-IgP (clogP = 3.30), gave positive results in computational docking, it unexpectedly presented greatly diminished binding to PKC in vitro. Through more rigorous computational molecular modeling, we reveal that, unlike HMI-1a3, PYR-1gP forms an intramolecular hydrogen bond, which both obstructs binding and reorients PYR-1gP in the membrane in a fashion that prevents it from correctly accessing the PKC C1 domain. Our results highlight the great value of molecular dynamics simulations as a key component for the drug design process of ligands targeting weakly membrane-associated proteins, where simulation in the relevant membrane environment is crucial for obtaining biologically applicable results. en
dc.format.extent 10
dc.language.iso eng
dc.relation.ispartof Journal of Chemical Information and Modeling
dc.rights unspecified
dc.rights.uri info:eu-repo/semantics/openAccess
dc.subject 116 Chemical sciences
dc.subject 317 Pharmacy
dc.title Rigorous computational study reveals what docking overlooks : Double trouble from membrane association in protein kinase C modulators en
dc.type Article
dc.contributor.organization Division of Pharmaceutical Biosciences
dc.contributor.organization Division of Pharmaceutical Chemistry and Technology
dc.contributor.organization Pharmaceutical biophysics group
dc.contributor.organization Department of Physics
dc.contributor.organization Drug Research Program
dc.contributor.organization Division of Pharmacology and Pharmacotherapy
dc.contributor.organization Regenerative cardiac pharmacology
dc.contributor.organization Regenerative pharmacology group
dc.contributor.organization Pharmaceutical Design and Discovery group
dc.description.reviewstatus Peer reviewed
dc.relation.doi https://doi.org/10.1021/acs.jcim.0c00624
dc.relation.issn 1549-9596
dc.rights.accesslevel openAccess
dc.type.version acceptedVersion

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