RESUMO
We studied the factors affecting the selectivity of peptidomimetic inhibitors of the highly homologous proteases matriptase and matriptase-2 across subpockets using docking simulations. We observed that the farther away a subpocket is located from the catalytic site, the more pronounced its role in selectivity. As a result of our exhaustive virtual screening, we biochemically validated novel potent and selective inhibitors of both enzymes.
Assuntos
Proteínas de Membrana/antagonistas & inibidores , Proteínas de Membrana/metabolismo , Serina Endopeptidases/metabolismo , Inibidores de Serina Proteinase/metabolismo , Domínio Catalítico , Humanos , Proteínas de Membrana/química , Simulação de Acoplamento Molecular , Estrutura Terciária de Proteína , Serina Endopeptidases/química , Inibidores de Serina Proteinase/farmacologia , Relação Estrutura-AtividadeRESUMO
Matriptase is a member of the type II transmembrane serine protease family. Several studies have reported deregulated matriptase expression in several types of epithelial cancers, suggesting that matriptase constitutes a potential target for cancer therapy. We report herein a new series of slow, tight-binding inhibitors of matriptase, which mimic the P1-P4 substrate recognition sequence of the enzyme. Preliminary structure-activity relationships indicate that this benzothiazole-containing RQAR-peptidomimetic is a very potent inhibitor and possesses a good selectivity for matriptase versus other serine proteases. A molecular model was generated to elucidate the key contacts between inhibitor 1 and matriptase.