A new lead for nonpeptidic active-site-directed inhibitors of the severe acute respiratory syndrome coronavirus main protease discovered by a combination of screening and docking methods
A new lead for nonpeptidic active-site-directed inhibitors of the severe acute respiratory syndrome coronavirus main protease discovered by a combination of screening and docking methods
复制标题
DOI：
10.1021/jm0501782
复制
发表时间：
2005-11-03
影响因子：
7.3
通讯作者：
Schirmeister, T
中科院分区：
文献类型：
--
作者：
Kaeppler, U;Stiefl, N;Schirmeister, T
冠状病毒的主要蛋白酶M-pro被认为是适用于对抗冠状病毒感染（包括严重急性呼吸综合征（SARS））的药物的主要靶标。为鉴定潜在的M-pro抑制剂而进行的亲电子化合物的基于HPLC的筛选显示依他尼酸叔丁基酰胺（6a）是有效的非肽抑制剂。对接的研究表明，结合模式，其中苯环作为一个间隔桥抑制剂的活化双键和其疏水叔丁基部分。后者被认为适合目标蛋白酶的S4口袋。此外，这些研究表明依他尼酸酰胺（6 b）作为非肽活性位点导向的M-pro抑制剂的一种有前途的先导化合物。在使用新的荧光共振能量转移（FRET）对标记的底物的荧光酶测定中，化合物6 b显示35.3 μ M的Ki值。由于新的先导化合物不靶向酶的底物结合口袋的S1 ′、S1和S2亚位点，因此存在强调化合物6 b的先导特征的改进空间。
The coronavirus main protease, M-pro, is considered to be a major target for drugs suitable for combating coronavirus infections including severe acute respiratory syndrome (SARS). An HPLC-based screening of electrophilic compounds that was performed to identify potential M-pro inhibitors revealed etacrynic acid tert-butylamide (6a) as an effective nonpeptidic inhibitor. Docking studies suggested a binding mode in which the phenyl ring acts as a spacer bridging the inhibitor's activated double bond and its hydrophobic tert-butyl moiety. The latter is supposed to fit into the S4 pocket of the target protease. Furthermore, these studies revealed etacrynic acid amide (6b) as a promising lead for nonpeptidic active-site-directed M-pro inhibitors. In a fluorimetric enzyme assay using a novel fluorescence resonance energy transfer (FRET) pair labeled substrate, compound 6b showed a K-i value of 35.3 mu M. Since the novel lead compound does not target the S1', S1, and S2 subsites of the enzyme's substrate-binding pockets, there is room for improvement that underlines the lead character of compound 6b.