基于计算机模拟的二肽基肽酶-IV S1口袋结合剂片段发现

In silico fragment-based discovery of DPP-IV S1 pocket binders.

作者信息

Rummey Christian, Nordhoff Sonja, Thiemann Meinolf, Metz Günther

机构信息

Computational Discovery, Santhera Pharmaceuticals, Im Neuenheimer Feld 518-519, 69120 Heidelberg, Germany.

出版信息

Bioorg Med Chem Lett. 2006 Mar 1;16(5):1405-9. doi: 10.1016/j.bmcl.2005.11.038.

DOI:10.1016/j.bmcl.2005.11.038

PMID:16321524

Abstract

Dipeptidyl peptidase IV is a clinically validated target for type-2 diabetes and belongs to a family of peptidases with a quite unique post-proline cleavage specificity. Known inhibitors contain a limited number of molecular anchors occupying the small prototypical S1 pocket. A virtual screening approach for such S1-binding fragments was carried out using FlexX docking to evaluate its potential to confirm known and find novel compounds. Several low molecular weight inhibitors exhibiting activities in the micromolar range could be identified as starting points for structure-based design.

摘要

二肽基肽酶IV是2型糖尿病的一个经过临床验证的靶点，属于具有相当独特的脯氨酸后切割特异性的肽酶家族。已知的抑制剂含有占据小的典型S1口袋的有限数量的分子锚。使用FlexX对接对这种S1结合片段进行了虚拟筛选方法，以评估其确认已知化合物和发现新化合物的潜力。几种在微摩尔范围内具有活性的低分子量抑制剂可被确定为基于结构设计的起点。