SARS-CoV-2Mpro(Mpro)是冠状病毒病毒复制中的关键半胱氨酸蛋白酶。茶多酚是有效的Mpro抑制剂。因此,我们的目标是从正热达白(ZHDB)白茶甲醇-水(MW)提取物中分离和合成更多可能抑制COVID-19的新型茶多酚。通过分子网络,共鉴定出33个化合物,并将其分为5个簇。Further,天然产物分子网络(MN)分析表明,MN1具有新的苯丙素取代酯-儿茶素(PSEC),MN5具有重要的碱性复合型羟基肉桂酰儿茶素(HCCs)。因此,分离出一个新的PSEC(1,PSEC636),可以在14个绿茶样品中进一步检测到。合成了一系列HCC(2-6),包括三个新的乙酰化HCC(3-5)。然后我们使用表面等离子体共振(SPR)分析了12种儿茶素与Mpro相互作用的平衡解离常数(KD)。PSEC636(1)的KD值,EGC-C(2),和EC-CDA(3)分别为2.25、2.81和2.44μM,分别。此外,化合物1、2和3显示出潜在的Mpro抑制作用,IC50为5.95±0.17、9.09±0.22和23.10±0.69μM,分别。Further,我们使用诱导配合对接(IFD),约束姿态元动力学(BPMD),和分子动力学(MD)探索Mpro-1的稳定结合状态,表明1可以与氨基酸残基THR26,HIS41,CYS44,TYR54,GLU166和ASP187紧密结合。计算机建模研究表明,酯,乙酰基,和邻苯三酚基团可以提高抑制活性。我们的研究表明,这些儿茶素是有效的Mpro抑制剂,并可能被开发为对抗COVID-19的治疗剂。
SARS-CoV-2 Mpro (Mpro) is the critical cysteine protease in coronavirus viral replication. Tea polyphenols are effective Mpro inhibitors. Therefore, we aim to isolate and synthesize more novel tea polyphenols from Zhenghedabai (ZHDB) white tea methanol-water (MW) extracts that might inhibit COVID-19. Through molecular networking, 33 compounds were identified and divided into 5 clusters. Further, natural products molecular network (MN) analysis showed that MN1 has new phenylpropanoid-substituted ester-catechin (PSEC), and MN5 has the important basic compound type hydroxycinnamoylcatechins (HCCs). Thus, a new PSEC (1, PSEC636) was isolated, which can be further detected in 14 green tea samples. A series of HCCs were synthesized (2-6), including three new acetylated HCCs (3-5). Then we used surface plasmon resonance (SPR) to analyze the equilibrium dissociation constants (KD) for the interaction of 12 catechins and Mpro. The KD values of PSEC636 (1), EGC-C (2), and EC-CDA (3) were 2.25, 2.81, and 2.44 μM, respectively. Moreover, compounds 1, 2, and 3 showed the potential Mpro inhibition with IC50 5.95 ± 0.17, 9.09 ± 0.22, and 23.10 ± 0.69 μM, respectively. Further, we used induced fit docking (IFD), binding pose metadynamics (BPMD), and molecular dynamics (MD) to explore the stable binding pose of Mpro-1, showing that 1 could tightly bond with the amino acid residues THR26, HIS41, CYS44, TYR54, GLU166, and ASP187. The computer modeling studies reveal that the ester, acetyl, and pyrogallol groups could improve inhibitory activity. Our research suggests that these catechins are effective Mpro inhibitors, and might be developed as therapeutics against COVID-19.