Biological evaluation and docking studies of natural isocoumarins as inhibitors for human kallikrein 5 and 7

Date
2011-10-15Author
Teixeira, Thiago S. P.
Freitas, Renato F.
Abrahao, Odonirio
Devienne, Karina F.
Souza, Lucas R. de
Blaber, Sachico I.
Blaber, Michael
Kondo, Marcia Y. [UNIFESP]
Juliano, Maria A. [UNIFESP]
Juliano, Luiz [UNIFESP]
Puzer, Luciano
Type
ArtigoISSN
0960-894XIs part of
Bioorganic & Medicinal Chemistry LettersDOI
10.1016/j.bmcl.2011.08.044Metadata
Show full item recordAbstract
Human kallikrein 5 and 7 (KLK5 and KLK7) are trypsin-like and chymotrypsin-like serine proteases, respectively, and promising targets for the treatment of skin desquamation, inflammation and cancer. in an effort to develop new inhibitors for these enzymes, we carried out enzymatic inhibition assays and docking studies with three isocoumarin compounds. Some promising inhibitors were uncovered, with vioxanthin and 8,8'-paepalantine being the most potent competitive inhibitors of KLK5 (K(i) = 22.9 mu M) and KLK7 (K(i) = 12.2 mu M), respectively. Our docking studies showed a good correlation with the experimental results, and revealed a distinct binding mode for the inhibitors at the binding sites of KLK5 and KLK7. in addition, the docking results suggested that the formation of hydrogen bonds at the oxyanion hole is essential for a good inhibitor. (C) 2011 Elsevier B.V. All rights reserved.
Citation
Bioorganic & Medicinal Chemistry Letters. Oxford: Pergamon-Elsevier B.V., v. 21, n. 20, p. 6112-6115, 2011.Sponsorship
Fundação de Amparo à Pesquisa do Estado de Minas Gerais (FAPEMIG)Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP)
Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq)
Coordenação de Aperfeiçoamento de Pessoal de Nível Superior (CAPES)
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