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dc.contributor.authorKalash, Leen
dc.contributor.authorCresser-Brown, Joel
dc.contributor.authorHabchi, Johnny
dc.contributor.authorMorgan, Connor
dc.contributor.authorMiller, David J
dc.contributor.authorGlen, Robert
dc.contributor.authorAllemann, Rudolf K
dc.contributor.authorBender, Andreas
dc.date.accessioned2018-11-14T00:30:47Z
dc.date.available2018-11-14T00:30:47Z
dc.date.issued2018-09-05
dc.identifier.issn0223-5234
dc.identifier.urihttps://www.repository.cam.ac.uk/handle/1810/285030
dc.description.abstractDimeric calpains constitute a promising therapeutic target for many diseases such as cardiovascular, neurodegenerative and ischaemic disease. The discovery of selective calpain inhibitors, however, has been extremely challenging. Previously, allosteric inhibitors of calpains, such as PD150606, which included a specific α-mercaptoacrylic acid sub-structure, were reported to bind to the penta-EF hand calcium binding domain, PEF(S) of calpain. Although these are selective to calpains over other cysteine proteases, their mode of action has remained elusive due to their ability to inhibit the active site domain with and without the presence of PEF(S), with similar potency. These findings have led to the question of whether the inhibitory response can be attributed to an allosteric mode of action or alternatively to inhibition at the active site. In order to address this problem, we report a structure-based virtual screening protocol as a novel approach for the discovery of PEF(S) binders that populate a novel chemical space. We have identified compound 1, Vidupiprant, which is shown to bind to the PEF(S) domain by the TNS displacement method, and it exhibited specificity in its allosteric mode of inhibition. Compound 1 inhibited the full-length calpain-1 complex with a higher potency (IC50 = 7.5 μM) than the selective, cell-permeable non-peptide calpain inhibitor, PD150606 (IC50 = 19.3 μM), where the latter also inhibited the active site domain in the absence of PEF(S) (IC50 = 17.8 μM). Hence the method presented here has identified known compounds with a novel allosteric mechanism for the inhibition of calpain-1. We show for the first time that the inhibition of enzyme activity can be attributed to an allosteric mode of action, which may offer improved selectivity and a reduced side-effects profile.
dc.format.mediumPrint-Electronic
dc.languageeng
dc.publisherElsevier BV
dc.subjectHumans
dc.subjectCalpain
dc.subjectGlycoproteins
dc.subjectAllosteric Regulation
dc.subjectMolecular Structure
dc.subjectStructure-Activity Relationship
dc.subjectDose-Response Relationship, Drug
dc.subjectDrug Design
dc.titleStructure-based design of allosteric calpain-1 inhibitors populating a novel bioactivity space.
dc.typeArticle
prism.endingPage1275
prism.publicationDate2018
prism.publicationNameEur J Med Chem
prism.startingPage1264
prism.volume157
dc.identifier.doi10.17863/CAM.32400
dcterms.dateAccepted2018-08-17
rioxxterms.versionofrecord10.1016/j.ejmech.2018.08.049
rioxxterms.licenseref.urihttp://www.rioxx.net/licenses/all-rights-reserved
rioxxterms.licenseref.startdate2018-09
dc.contributor.orcidGlen, Robert [0000-0003-1759-2914]
dc.contributor.orcidBender, Andreas [0000-0002-6683-7546]
dc.identifier.eissn1768-3254
rioxxterms.typeJournal Article/Review
pubs.funder-project-idEuropean Research Council (336159)
rioxxterms.freetoread.startdate2019-09-30


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