Structure Based Library Design (SBLD) for new 1,4-dihydropyrimidine scaffold as simultaneous COX-1/COX-2 and 5-LOX inhibitors
Structure Based Library Design (SBLD) for new 1,4-dihydropyrimidine scaffold as simultaneous COX-1/COX-2 and 5-LOX inhibitors
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DOI：
10.1016/j.bmc.2015.06.008
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发表时间：
2015-08-01
影响因子：
3.5
通讯作者：
Shinde, Devanand
中科院分区：
文献类型：
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作者：
Lokwani, Deepak;Azad, Rajaram;Shinde, Devanand
考虑COX-1/COX-2和5-LOX酶活性位点的环境，设计了各种含有1,4-二氢嘧啶环的支架。基于结构的文库设计方法，包括重点文库设计（虚拟组合文库设计）和虚拟筛选，用于选择同时抑制两种酶途径（COX-1/COX-2和5-LOX）的1,4-二氢嘧啶支架。每个 1,4-二氢嘧啶支架上的虚拟文库以两种替代方式进行计数。第一种方式，通过单位置取代的支架对接来过滤R基团上的化学试剂，即使用Glide XP对接模式仅在COX-2酶上的R-1、或R-2、或R-3、...R-n处。去除对接不好的结构，并用过滤的化学试剂对文库进行计数。在第二种替代方式中，绕过单位置对接阶段，并且通过对接COX-2酶使用所有化学试剂对整个文库进行计数。在筛选药物样特性后，通过这两种方式获得的大约 15,629 种化合物的整个库，使用虚拟筛选工作流程进一步筛选它们对 COX-1 和 5-LOX 酶的结合亲和力。最后，获得了 142 个命中，并根据它们对 COX-1/COX-2 和两种酶途径（COX-1/COX-2 和 5-LOX）的结合亲和力分为两组。选择、合成了这十种分子，并评估了它们的 COX-1、COX-2 和 5-LOX 抑制活性。 (C) 2015 Elsevier Ltd. 保留所有权利。
The various scaffolds containing 1,4-dihydropyrimidine ring were designed by considering the environment of the active site of COX-1/COX-2 and 5-LOX enzymes. The structure-based library design approach, including the focused library design (Virtual Combinatorial Library Design) and virtual screening was used to select the 1,4-dihydropyrimidine scaffold for simultaneous inhibition of both enzyme pathways (COX-1/COX-2 and 5-LOX). The virtual library on each 1,4-dihydropyrimidine scaffold was enumerated in two alternative ways. In first way, the chemical reagents at R groups were filtered by docking of scaffold with single position substitution, that is, only at R-1, or R-2, or R-3, ... R-n on COX-2 enzyme using Glide XP docking mode. The structures that do not dock well were removed and the library was enumerated with filtered chemical reagents. In second alternative way, the single position docking stage was bypassed, and the entire library was enumerated using all chemical reagents by docking on the COX-2 enzyme. The entire library of approximately 15,629 compounds obtained from both ways after screening for drug like properties, were further screened for their binding affinity against COX-1 and 5-LOX enzymes using Virtual Screening Workflow. Finally, 142 hits were obtained and divided into two groups based on their binding affinity for COX-1/COX-2 and for both enzyme pathways (COX-1/COX-2 and 5-LOX). The ten molecules were selected, synthesized and evaluated for their COX-1, COX-2 and 5-LOX inhibiting activity. (C) 2015 Elsevier Ltd. All rights reserved.