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

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.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)Univ Fed ABC, Ctr Ciencias Nat & Humanas, BR-09210170 Santo Andre, SP, BrazilUniv Fed Triangulo Mineiro, Inst Ciencias Biol & Nat, Uberaba, MG, BrazilFlorida State Univ, Dept Biomed Sci, Tallahassee, FL 32306 USAUniversidade Federal de São Paulo, Dept Biofis, São Paulo, BrazilUniversidade Federal de São Paulo, Dept Biofis, São Paulo, BrazilFAPESP: 06/53607-6CNPq: 312701/2009-8Web of Scienc