Novel human mPGES-1 inhibitors identified through structure-based virtual screening.
Novel human mPGES-1 inhibitors identified through structure-based virtual screening.
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DOI：
10.1016/j.bmc.2011.08.040
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发表时间：
2011-10-15
影响因子：
3.5
通讯作者：
Zhan, Chang-Guo
中科院分区：
文献类型：
--
作者：
Hamza, Adel;Zhao, Xinyun;Tong, Min;Tai, Hsin-Hsiung;Zhan, Chang-Guo
微粒体前列腺素E合成酶-1(mPGES-1)是一种受促炎刺激诱导的前列腺素E合成酶，是治疗急、慢性炎症性疾病的新靶点。寻找具有新型支架的mPGES-1抑制剂作为新的先导或靶点，对于开发下一代抗炎药物的药物设计和发现具有重要意义。在此，我们报道了通过大规模基于结构的虚拟筛选、灵活对接、分子动力学模拟、结合自由能计算和体外实验对计算选择的化合物的实际抑制活性进行鉴定的新型mPGES-1抑制剂。计算研究是基于我们最近开发的mPGES-1开放状态的三维(3D)结构模型。计算和实验相结合的研究已经导致了新的mPGES-1抑制剂与新的支架的识别。特别是(Z)-5-亚甲基-2-亚氨基噻唑烷-4-酮，为进一步合理设计和发现新型mPGES-1抑制剂提供了一个很有前途的新型支架。据我们所知，这是首次将开放状态mPGES-1的三维结构模型用于基于结构的虚拟筛选大量可用于mPGES-1抑制剂鉴定的化合物文库。积极的实验结果表明，我们最近建立的mPGES-1开放状态的三聚体结构已经为基于结构的药物设计和发现做好了准备。
Microsomal prostaglandin E synthase-1 (mPGES-1) is an inducible prostaglandin E synthase after exposure to pro-inflammatory stimuli and, therefore, represents a novel target for therapeutic treatment of acute and chronic inflammatory disorders. It is essential to identify mPGES-1 inhibitors with novel scaffolds as new leads or hits for the purpose of drug design and discovery that aim to develop the next-generation anti-inflammatory drugs. Herein we report novel mPGES-1 inhibitors identified through a combination of large-scale structure-based virtual screening, flexible docking, molecular dynamics simulations, binding free energy calculations, and in vitro assays on the actual inhibitory activity of the computationally selected compounds. The computational studies are based on our recently developed three-dimensional (3D) structural model of mPGES-1 in its open state. The combined computational and experimental studies have led to identification of new mPGES-1 inhibitors with new scaffolds. In particular, (Z)-5-benzylidene-2-iminothiazolidin-4-one is a promising novel scaffold for the further rational design and discovery of new mPGES-1 inhibitors. To our best knowledge, this is the first time a 3D structural model of the open-state mPGES-1 is used in structure-based virtual screening of a large library of available compounds for the mPGES-1 inhibitor identification. The positive experimental results suggest that our recently modeled trimeric structure of mPGES-1 in its open state is ready for the structure-based drug design and discovery.
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影响因子：
8
作者：
GUENOT, J;KOLLMAN, PA
通讯作者：
KOLLMAN, PA
影响因子：
3.3
作者：
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通讯作者：
Zhan, CG
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作者：
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通讯作者：
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影响因子：
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作者：
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通讯作者：
FREER, ST