Instituto de Ciências Biológicas e Naturais, Universidade Federal do Triângulo Mineiro, Uberaba, MG, Brazil.
Bioorg Med Chem Lett. 2011 Oct 15;21(20):6112-5. doi: 10.1016/j.bmcl.2011.08.044. Epub 2011 Aug 16.
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 μM) and KLK7 (K(i)=12.2 μM), 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.
人激肽释放酶 5 和 7（KLK5 和 KLK7）分别是胰凝乳蛋白酶样和糜蛋白酶样丝氨酸蛋白酶，是治疗皮肤脱皮、炎症和癌症的有前途的靶点。为了开发这些酶的新抑制剂，我们用三种异香豆素化合物进行了酶抑制测定和对接研究。发现了一些有希望的抑制剂，其中，violaxanthin 和 8,8'-paepalantine 分别是 KLK5（K(i)=22.9 μM）和 KLK7（K(i)=12.2 μM）的最有效竞争性抑制剂。我们的对接研究与实验结果具有很好的相关性，并揭示了抑制剂在 KLK5 和 KLK7 结合位点的独特结合模式。此外，对接结果表明，在氧阴离子穴形成氢键对于良好的抑制剂是必不可少的。
