| Texto completo | |
| Autor(es): Mostrar menos - |
Freitas, Renato F.
[1]
;
Teixeira, Thiago S. P.
[1]
;
Barros, Thalita G.
[2]
;
Santos, Jorge A. N.
;
Kondo, Marcia Y.
[3]
;
Juliano, Maria A.
[3]
;
Juliano, Luiz
[3]
;
Blaber, Michael
[4]
;
Antunes, Octavio A. C.
[5]
;
Abrahao, Jr., Odonirio
[1]
;
Pinheiro, Sergio
[6]
;
Muri, Estela M. F.
[2]
;
Puzer, Luciano
[7, 1]
Número total de Autores: 13
|
| Afiliação do(s) autor(es): | [1] Univ Fed Triangulo Mineiro, Inst Ciencias Biol & Nat, Uberaba, MG - Brazil
[2] Univ Fed Fluminense, Fac Farm, Niteroi, RJ - Brazil
[3] Univ Fed Sao Paulo, Dept Biofis, Sao Paulo, SP - Brazil
[4] Florida State Univ, Dept Biomed Sci, Tallahassee, FL 32306 - USA
[5] Univ Fed Rio de Janeiro, Inst Quim, Rio De Janeiro, RJ - Brazil
[6] Univ Fed Fluminense, Inst Quim, Niteroi, RJ - Brazil
[7] Univ Fed ABC, Ctr Ciencias Nat & Humanas, BR-09210170 Santo Andre, SP - Brazil
Número total de Afiliações: 7
|
| Tipo de documento: | Artigo Científico |
| Fonte: | Bioorganic & Medicinal Chemistry Letters; v. 22, n. 19, p. 6072-6075, OCT 1 2012. |
| Citações Web of Science: | 16 |
| Resumo | |
Human 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 Ltd. All rights reserved. (AU) | |
| Processo FAPESP: | 11/51297-8 - Desenvolvimento de inibidores para as calicreínas teciduais humanas 5 e 7 (KLK5 e KLK7) |
| Beneficiário: | Luciano Puzer |
| Modalidade de apoio: | Auxílio à Pesquisa - Regular |