Development of potent dipeptide-type SARS-CoV 3CL protease inhibitors with novel P3 scaffolds: design, synthesis, biological evaluation, and docking studies.
Development of potent dipeptide-type SARS-CoV 3CL protease inhibitors with novel P3 scaffolds: design, synthesis, biological evaluation, and docking studies.
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DOI：
10.1016/j.ejmech.2013.07.037
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发表时间：
2013-10
影响因子：
6.7
通讯作者：
Hayashi Y
中科院分区：
文献类型：
--
作者：
Thanigaimalai P;Konno S;Yamamoto T;Koiwai Y;Taguchi A;Takayama K;Yakushiji F;Akaji K;Chen SE;Naser-Tavakolian A;Schön A;Freire E;Hayashi Y
我们设计和合成了一系列具有新型P3支架的二肽型抑制剂，这些抑制剂对SARS-CoV 3CLpro具有有效的抑制活性。一项涉及二肽先导化合物4与3CLpro结合的对接研究表明，4中的各种刚性P3基团修饰了结构灵活的P3 N-（3-甲氧基苯基）甘氨酸。这些修饰导致鉴定出几种有效的衍生物，包括5c-k和5n，其抑制活性（Ki或IC50）在亚微摩尔到纳摩尔范围内。其中化合物5h表现出最强的抑制活性，Ki值为0.006 μM。该效价比先导化合物4 （Ki = 0.39 μM）的效价高65倍。此外，5h的Ki值与等温滴定量热法（ITC）观察到的结合亲和力（16 nM）非常吻合。一项针对P3基团的SAR研究发现，一个刚性的吲哚-2-羰基单元是最好的P3基团之一（5c）。进一步优化表明，吲哚基4位的甲氧基取代有利于提高抑制效能。合成了一系列低分子量二肽型抗sars药物。化合物已显示出有效的抑制活性。通过引入P3吲哚-2-羰基单元，发现了有效的先导化合物。化合物5h表现出良好的抑制活性，K i值为6.0 nM。
We report the design and synthesis of a series of dipeptide-type inhibitors with novel P3 scaffolds that display potent inhibitory activity against SARS-CoV 3CLpro. A docking study involving binding between the dipeptidic lead compound 4 and 3CLpro suggested the modification of a structurally flexible P3 N-(3-methoxyphenyl)glycine with various rigid P3 moieties in 4. The modifications led to the identification of several potent derivatives, including 5c–k and 5n with the inhibitory activities (Ki or IC50) in the submicromolar to nanomolar range. Compound 5h, in particular, displayed the most potent inhibitory activity, with a Ki value of 0.006 μM. This potency was 65-fold higher than the potency of the lead compound 4 (Ki = 0.39 μM). In addition, the Ki value of 5h was in very good agreement with the binding affinity (16 nM) observed in isothermal titration calorimetry (ITC). A SAR study around the P3 group in the lead 4 led to the identification of a rigid indole-2-carbonyl unit as one of the best P3 moieties (5c). Further optimization showed that a methoxy substitution at the 4-position on the indole unit was highly favorable for enhancing the inhibitory potency. A series of low-molecular-weight dipeptide-type anti-SARS agents were synthesized. Compounds have shown potent inhibitory activities. Discovery of potent lead compound was achieved by introducing P3 indole-2-carbonyl unit. Compounds 5h exhibited excellent inhibitory activity with K i value of 6.0 nM.
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影响因子：
1.8
作者：
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通讯作者：
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影响因子：
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