Scaffold-Hopping Cascade Yields Potent Inhibitors of 5-Lipoxygenase
Scaffold-Hopping Cascade Yields Potent Inhibitors of 5-Lipoxygenase
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DOI：
10.1002/cmdc.200800153
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发表时间：
2008-10-01
期刊：
影响因子：
3.4
通讯作者：
Schneider, Gisbert
中科院分区：
文献类型：
--
作者：
Hofmann, Bettina;Franke, Lutz;Schneider, Gisbert
Bettina Hofmann，[a]Lutz Franke，[a]Ewgenij Proschak，[a]Yusuf Tanrikulu，[a]Petra Schneider，[b]Dieter Steinhelber，[c]和Gisbert Schneider*[a]5-Lo是治疗炎症和过敏反应的有效药物靶点，因为这种酶参与催化花生四烯酸转化为白三烯。抗炎和平喘药没有选择性COX抑制剂的胃肠道副作用。[3]最近，5-LO/COX-2双重抑制剂被认为是潜在的抗癌药物。[4]在本研究中，基于配体的虚拟筛选方法以迭代的方式寻找新的5-LO产物形成的抑制剂。这项研究包括四个后续的虚拟筛选周期，包括基于3D和2D的方法和子结构搜索，以及生化测试。这些迭代步骤导致了在细胞实验中发现具有纳米分子抑制活性的基于吡啶-咪唑的先导结构系列，展示了先进的虚拟筛选技术在设计小的、集中的、在基于细胞的分析中产生高命中率的筛选文库中的适用性。我们从文献(支持信息，图S1)，[5]中选择11个双5-LO/COX参考抑制剂，目的是探索基于配体的虚拟筛选方法从大型化合物集合中检索具有不同骨架结构的相同功能的化学型(支架跳跃)[6]的能力。第一步是按照图1中概述的方案进行广泛的虚拟筛选过程。对于11个查询中的每一个，使用“Charge3D”[7，8]和“TripleCharge3D”[7，9]方法在Asinex Gold(2005年11月：231812个化合物)和PlatGold(132250个化合物)集合(Asinex Ltd.，莫斯科，俄罗斯)中执行两次无对齐相似性搜索。
Bettina Hofmann,[a] Lutz Franke,[a] Ewgenij Proschak,[a] Yusuf Tanrikulu,[a] Petra Schneider,[b] Dieter Steinhilber,[c] and Gisbert Schneider*[a]5-lipoxygenase (5-LO) is a validated drug target for the treatment of inflammation and allergic reactions as this enzyme is involved in catalyzing the conversion of arachidonic acid into leukotrienes.[1] Inhibitors with dual activity towards both 5-LO and cyclooxygenase (COX), such as Licofelone,[2] have been described as potent analgesic, anti-inflammatory and antiasthmatic agents lacking the gastrointestinal side effects seen with selective COX inhibitors.[3] More recently, dual 5-LO/COX-2 inhibitors have been suggested as potential anticancer drugs.[4] In this study, ligand-based virtual screening methods were used in an iterative fashion to identify new inhibitors of 5-LO product formation. The study consisted of four subsequent cycles of virtual screening, including 3D-and 2D-based methods and substructure searching, as well as biochemical testing. The iterative steps led to the discovery of a pyridine–imidazole-based lead structure series with nanomolar inhibitory activity in a cellular assay, demonstrating the applicability of advanced virtual screening techniques for designing small, focused, screening libraries that yield high hit rates in cell-based assays.We selected 11 dual 5-LO/COX reference inhibitors from the literature (Supporting Information, figure S1),[5] with the aim to explore the ability of ligand-based virtual screening methods to retrieve isofunctional chemotypes with different backbone architecture (“scaffold-hopping”)[6] from a large compound collection. The first step involved a broad, virtual screening process following the protocol outlined in Figure 1. For each of the 11 queries, two alignment-free similarity searches were performed in the Asinex Gold (November 2005: 231812 compounds) and Platinum (132 250 compounds) collections (Asinex Ltd., Moscow, Russia) using the “Charge3D”[7, 8] and “TripleCharge3D”[7, 9] methods.