Virtual screening and optimization yield low-nanomolar inhibitors of the tautomerase activity of Plasmodium falciparum macrophage migration inhibitory factor.
Virtual screening and optimization yield low-nanomolar inhibitors of the tautomerase activity of Plasmodium falciparum macrophage migration inhibitory factor.
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DOI：
10.1021/jm301269s
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发表时间：
2012-11-26
影响因子：
7.3
通讯作者：
Jorgensen, William L.
中科院分区：
文献类型：
--
作者：
Dahlgren, Markus K.;Garcia, Alvaro Baeza;Hare, Alissa A.;Tirado-Rives, Julian;Leng, Lin;Bucala, Richard;Jorgensen, William L.
人细胞因子巨噬细胞迁移抑制因子（PfMIF）的恶性疟原虫直系同源物由寄生虫在疟疾感染期间产生并调节宿主的免疫应答。与其他MIF同源物一样，PfMIF具有互变异构酶活性，其抑制可能影响细胞因子活性。为了鉴定PfMIF互变异构酶活性的小分子抑制剂，通过将210万种化合物对接到酶位点中进行了虚拟筛选。对17种化合物的分析确定了4种具有活性。对这些化合物中最有效的4-苯氧基吡啶类似物的子结构搜索，鉴定了另外四种购买的化合物，并且也显示出活性。然后设计、合成并测定了31个额外的类似物。三个被发现是有效的PfMIF互变异构酶抑制剂，Ki值约为。40 nM;它们对人MIF也具有高度选择性，Ki值>100 μM。
The Plasmodium falciparum ortholog of the human cytokine, macrophage migratory inhibitory factor (PfMIF), is produced by the parasite during malaria infection and modulates the host’s immune response. As for other MIF orthologs, PfMIF has tautomerase activity, whose inhibition may influence the cytokine activity. To identify small-molecule inhibitors of the tautomerase activity of PfMIF, virtual screening has been performed by docking 2.1 million compounds into the enzymatic site. Assaying of 17 compounds identified four as active. Substructure search for the most potent of these compounds, a 4-phenoxypyridine analogue, identified four additional compounds that were purchased and also shown to be active. Thirty-one additional analogues were then designed, synthesized, and assayed. Three were found to be potent PfMIF tautomerase inhibitors with Ki values of ca. 40 nM; they are also highly selective with Ki values of >100 μM for human MIF.
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影响因子：
2.7
作者：
Jorgensen, William L.;Gandavadi, Sunilkumar;Bucala, Richard
通讯作者：
Bucala, Richard
影响因子：
2.7
作者：
Hare, Alissa A.;Leng, Lin;Gandavadi, Sunilkumar;Du, Xin;Cournia, Zoe;Bucala, Richard;Jorgensen, William L.
通讯作者：
Jorgensen, William L.
影响因子：
3
作者：
Pettersen, EF;Goddard, TD;Ferrin, TE
通讯作者：
Ferrin, TE
影响因子：
4.4
作者：
Kamir, Daniela;Zierow, Swen;Bucala, Richard
通讯作者：
Bucala, Richard
影响因子：
5.6
作者：
Jones, G;Willett, P;Taylor, R
通讯作者：
Taylor, R