Discovery of Camellia sinensis catechins as SARS-CoV-2 3CL protease inhibitors through molecular docking, intra and extra cellular assays.
Discovery of Camellia sinensis catechins as SARS-CoV-2 3CL protease inhibitors through molecular docking, intra and extra cellular assays.
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DOI：
10.1016/j.phymed.2021.153853
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发表时间：
2022-03
期刊：
影响因子：
--
通讯作者：
Bao GH
中科院分区：
文献类型：
--
作者：
Liu SY;Wang W;Ke JP;Zhang P;Chu GX;Bao GH
以往的研究表明，主要的茶树（茶）儿茶素可以抑制3-糜蛋白酶样半胱氨酸蛋白酶（3CLpro），启发我们研究3CLpro抑制最近发现的茶叶儿茶素。利用Autodock对3CLpro和16种茶儿茶素进行了对接。此外，使用3CLpro活性检测系统来测试它们的细胞内和细胞外3CLpro抑制活性。采用表面等离子体共振（SPR）技术分析了儿茶素与3CLpro的解离常数（KD）。对接结果表明，3CLpro与16种儿茶素类化合物通过关键氨基酸Thr 24、Thr 26、Asn 142、Gly 143、His 163和Gln 189相互作用，结合能较低。除了紫藤素D（3）和（-）-8-（5-Mobi’R）-N-乙基-2-吡咯烷酮-3-O-肉桂酰表儿茶素（11）外，所选的儿茶素类物质均能在细胞内抑制3CLpro。（-）-表儿茶素3-O-咖啡酸酯（EC-C，1）、紫藤素C（2）、等-吡咯烷酮C和D（6）、等-吡咯烷酮A（9）、（+）-没食子儿茶素没食子酸酯（GCG）和（-）-表儿茶素没食子酸酯（ECG）的细胞外3CLpro IC 50值分别为1.58 ± 0.21、41.2 ± 3.56、0.90 ± 0.03、分别为46.71 ± 10.50、3.38 ± 0.48和71.78 ± 8.36 µM。1、6和GCG的KD值分别为4.29、3.46和3.36 µM。EC-C（1）、etc-pyrrolidinone C和D（6）和GCG一起是强3CLpro抑制剂。我们的研究结果表明，儿茶素的结构修饰可以通过取代3-OH以及改变C-3，C-3 Mobi“或C-5 Mobi”的构型来进行，以发现强的SARS-CoV-2抑制剂。
Previous studies suggest that major Camellia sinensis (tea) catechins can inhibit 3-chymotrypsin-like cysteine protease (3CLpro), inspiring us to study 3CLpro inhibition of the recently discovered catechins from tea by our group. Autodock was used to dock 3CLpro and 16 tea catechins. Further, a 3CLpro activity detection system was used to test their intra and extra cellular 3CLpro inhibitory activity. Surface plasmon resonance (SPR) was used to analyze the dissociation constant (KD) between the catechins and 3CLpro. Docking data suggested that 3CLpro interacted with the selected 16 catechins with low binding energy through the key amino acid residues Thr24, Thr26, Asn142, Gly143, His163, and Gln189. The selected catechins other than zijuanin D (3) and (-)-8-(5′'R)-N-ethyl-2-pyrrolidinone-3-O-cinnamoylepicatechin (11) can inhibit 3CLpro intracellularly. The extracellular 3CLpro IC50 values of (–)-epicatechin 3-O-caffeoate (EC-C, 1), zijuanin C (2), etc-pyrrolidinone C and D (6), etc-pyrrolidinone A (9), (+)-gallocatechin gallate (GCG), and (-)-epicatechin gallate (ECG) are 1.58 ± 0.21, 41.2 ± 3.56, 0.90 ± 0.03, 46.71 ± 10.50, 3.38 ± 0.48, and 71.78 ± 8.36 µM, respectively. The KD values of 1, 6, and GCG are 4.29, 3.46, and 3.36 µM, respectively. Together, EC-C (1), etc-pyrrolidinone C and D (6), and GCG are strong 3CLpro inhibitors. Our results suggest that structural modification of catechins could be conducted by esterificating the 3-OH as well as changing the configuration of C-3, C-3′'' or C-5′'' to discover strong SARS-CoV-2 inhibitors.
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