Molecular Connectivity & Drug Design Research Unit, Department of Physical Chemistry, Faculty of Pharmacy, University of Valencia, Avenida V.A. Estelles s/n, Burjasot, 46100 , Valencia, Spain.
Mol Divers. 2013 Aug;17(3):573-93. doi: 10.1007/s11030-013-9458-6. Epub 2013 Jun 23.
Ulcerative colitis (UC) is an immune-mediated chronic and relapsing intestinal inflammatory disease. Interleukin (IL)-6, a pro-inflammatory cytokine, plays a key role in the uncontrolled intestinal inflammatory process, which is a main characteristic of UC. In this work, a quantitative structure-activity relationship model based on molecular topology (MT) has been built up to predict the IL-6 mediated anti-UC activity. After an external validation of the model, a virtual screening of the MicroSource Pure Natural Products Collection and Sigma-Aldrich databases was carried out looking for potential new active compounds. From the entire set of compounds labeled as active by the model, four of them, namely alizarin-3-methylimino-N,N-diacetic acid (AMA), Calcein, (+)-dibenzyl-L-tartrate (DLT), and Ro 41-0960, were tested in vitro by determination of IL-6 production in two cell lines (RAW 264.7 and Caco-2). The results demonstrate that three of them were able to significantly reduce IL-6 levels in both cell lines and particularly one, namely Ro 41-0960. These results confirm MT's efficacy as a tool for the selection of compounds potentially active in UC.
溃疡性结肠炎（UC）是一种免疫介导的慢性和复发性肠道炎症性疾病。白细胞介素（IL）-6 是一种促炎细胞因子，在不受控制的肠道炎症过程中发挥关键作用，这是 UC 的主要特征。在这项工作中，建立了基于分子拓扑学（MT）的定量构效关系模型，以预测 IL-6 介导的抗 UC 活性。对模型进行外部验证后，对 MicroSource Pure Natural Products Collection 和 Sigma-Aldrich 数据库进行了虚拟筛选，寻找潜在的新活性化合物。在所标记的具有活性的整个化合物集中，有四种化合物，即茜素-3-甲基亚氨基-N，N-二乙酸（AMA）、钙黄绿素、（+）-二苄基-L-酒石酸（DLT）和 Ro 41-0960，在两种细胞系（RAW 264.7 和 Caco-2）中通过测定 IL-6 产生来进行体外测试。结果表明，其中三种化合物在两种细胞系中均能显著降低 IL-6 水平，特别是一种化合物 Ro 41-0960。这些结果证实了 MT 作为选择 UC 中潜在活性化合物的工具的有效性。
