使用定量构效关系辅助虚拟筛选策略发现人肠道二肽/三肽转运体（hPEPT1）的配体。

Discovery of ligands for the human intestinal Di-/Tripeptide transporter (hPEPT1) using a QSAR-assisted virtual screening strategy.

作者信息

Larsen Simon Birksø, Omkvist Diana Højmark, Brodin Birger, Nielsen Carsten Uhd, Steffansen Bente, Olsen Lars, Jørgensen Flemming Steen

机构信息

Department of Medicinal Chemistry, Faculty of Pharmaceutical Sciences, University of Copenhagen, 2 Universitetsparken, 2100 Copenhagen, Denmark.

出版信息

ChemMedChem. 2009 Sep;4(9):1439-45. doi: 10.1002/cmdc.200900145.

DOI:10.1002/cmdc.200900145

PMID:19557803

Abstract

The discovery of novel ligands for the hPEPT1 transporter is reported. By exploiting a fast and rigorously validated QSAR model in combination with the distance in activity-centered chemical space (DACCS) approach, a database of commercially available compounds (Sigma-Aldrich) was screened for virtual hits. Twelve compounds were then purchased and characterized in an apical [14C]Gly-Sar uptake competition assay. Four compounds displayed affinity in the medium-to-high range. A simple benzophenone derivative displayed high affinity with a sub-millimolar binding constant (Ki=0.24 mM). The results of this study will serve as starting points for future projects, including the design and synthesis of compound libraries that seek to systematically explore the fundamental requirements for binding and transport by hPEPT1.

摘要

报道了人肽转运体1（hPEPT1）新型配体的发现。通过利用快速且经过严格验证的定量构效关系（QSAR）模型，并结合以活性为中心的化学空间距离（DACCS）方法，对一个市售化合物数据库（西格玛奥德里奇公司）进行虚拟筛选以寻找命中化合物。随后购买了12种化合物，并在顶侧[14C]甘氨酰 - 肌氨酸摄取竞争试验中对其进行表征。4种化合物表现出中等到高亲和力范围的亲和力。一种简单的二苯甲酮衍生物表现出高亲和力，结合常数为亚毫摩尔级（Ki = 0.24 mM）。本研究结果将作为未来项目的起点，包括设计和合成化合物库，旨在系统地探索hPEPT1结合和转运的基本要求。