Isomannide derivatives as new class of inhibitors for human kallikrein 7

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dc.contributor.authorFreitas, Renato F.
dc.contributor.authorTeixeira, Thiago S. P.
dc.contributor.authorBarros, Thalita G.
dc.contributor.authorSantos, Jorge A. N.
dc.contributor.authorKondo, Marcia Y. [UNIFESP]
dc.contributor.authorJuliano, Maria A. [UNIFESP]
dc.contributor.authorJuliano, Luiz [UNIFESP]
dc.contributor.authorBlaber, Michael
dc.contributor.authorAntunes, Octavio A. C.
dc.contributor.authorAbrahao, Odonirio
dc.contributor.authorPinheiro, Sergio
dc.contributor.authorMuri, Estela M. F.
dc.contributor.authorPuzer, Luciano
dc.contributor.institutionUniv Fed Triangulo Mineiro
dc.contributor.institutionUniversidade Federal Fluminense (UFF)
dc.contributor.institutionUniversidade Federal de São Paulo (UNIFESP)
dc.contributor.institutionFlorida State Univ
dc.contributor.institutionUniversidade Federal do Rio de Janeiro (UFRJ)
dc.contributor.institutionUniversidade Federal do ABC (UFABC)
dc.date.accessioned2016-01-24T14:27:50Z
dc.date.available2016-01-24T14:27:50Z
dc.date.issued2012-10-01
dc.description.abstractHuman kallikrein 7 (KLK7) is a potential target for the treatment of skin inflammation and cancer. Despite its potential, few KLK7-specific small-molecule inhibitors have been reported in the literature. As an extension of our program to design serine protease inhibitors, here we describe the in vitro assays and the investigation of the binding mechanism by molecular dynamics simulation of a novel class of pseudo-peptide inhibitors derived from isomannide. of the inhibitors tested, two inhibited KLK7 with K-i values in the low micromolar range (9g = 1.8 mu M; 9j = 3.0 mu M). Eadie-Hofstee and Dixon plots were used to evaluate the competitive mechanism of inhibition for the molecules. Calculated binding free energies using molecular MM/PB(GB) SA approach are in good agreement with experimental results, suggesting that the inhibitors share the same binding mode, which is stabilized by hydrophobic interactions and by a conserved network of hydrogen bonds. the promising results obtained in this study make these compounds valid leads for further optimization studies aiming to improve the potency of this new class of kallikrein inhibitors. (C) 2012 Elsevier B.V. All rights reserved.en
dc.description.affiliationUniv Fed Triangulo Mineiro, Inst Ciencias Biol & Nat, Uberaba, MG, Brazil
dc.description.affiliationUniv Fed Fluminense, Fac Farm, Niteroi, RJ, Brazil
dc.description.affiliationUniversidade Federal de São Paulo, Dept Biofis, São Paulo, SP, Brazil
dc.description.affiliationFlorida State Univ, Dept Biomed Sci, Tallahassee, FL 32306 USA
dc.description.affiliationUniv Fed Rio de Janeiro, Inst Quim, Rio de Janeiro, RJ, Brazil
dc.description.affiliationUniv Fed Fluminense, Inst Quim, Niteroi, RJ, Brazil
dc.description.affiliationUniv Fed ABC, Ctr Ciencias Nat & Humanas, BR-09210170 Santo Andre, SP, Brazil
dc.description.affiliationUnifespUniversidade Federal de São Paulo, Dept Biofis, São Paulo, SP, Brazil
dc.description.sourceWeb of Science
dc.description.sponsorshipFundação de Amparo à Pesquisa do Estado de Minas Gerais (FAPEMIG)
dc.description.sponsorshipFundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP)
dc.description.sponsorshipConselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq)
dc.description.sponsorshipCoordenação de Aperfeiçoamento de Pessoal de Nível Superior (CAPES)
dc.description.sponsorshipIDFAPESP: 11/51297-8
dc.description.sponsorshipIDCNPq: 312701/2009-8
dc.format.extent6072-6075
dc.identifierhttp://dx.doi.org/10.1016/j.bmcl.2012.08.047
dc.identifier.citationBioorganic & Medicinal Chemistry Letters. Oxford: Pergamon-Elsevier B.V., v. 22, n. 19, p. 6072-6075, 2012.
dc.identifier.doi10.1016/j.bmcl.2012.08.047
dc.identifier.issn0960-894X
dc.identifier.urihttp://repositorio.unifesp.br/handle/11600/35364
dc.identifier.wosWOS:000309105200007
dc.language.isoeng
dc.publisherElsevier B.V.
dc.relation.ispartofBioorganic & Medicinal Chemistry Letters
dc.rightsinfo:eu-repo/semantics/restrictedAccess
dc.rights.licensehttp://www.elsevier.com/about/open-access/open-access-policies/article-posting-policy
dc.subjectSerine proteaseen
dc.subjectKallikreinen
dc.subjectPseudo-peptideen
dc.subjectInhibitoren
dc.subjectMolecular dynamicsen
dc.titleIsomannide derivatives as new class of inhibitors for human kallikrein 7en
dc.typeinfo:eu-repo/semantics/article
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