Exploring new catechin derivatives as SARS-CoV-2 M(pro) inhibitors from tea by molecular networking, surface plasma resonance, enzyme inhibition, induced fit docking, and metadynamics simulations.
Exploring new catechin derivatives as SARS-CoV-2 M(pro) inhibitors from tea by molecular networking, surface plasma resonance, enzyme inhibition, induced fit docking, and metadynamics simulations.
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DOI：
10.1016/j.compbiomed.2022.106288
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发表时间：
2022-12
影响因子：
7.7
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中科院分区：
文献类型：
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SARS-CoV-2 Mpro（Mpro）是冠状病毒复制过程中的关键半胱氨酸蛋白酶。茶多酚是有效的Mpro抑制剂。因此，我们的目标是从郑和大白（ZHDB）白色茶甲醇-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。通过分子网络分析，共鉴定出33个化合物，并将其分为5个簇。天然产物分子网络（MN）分析表明，MN 1含有新的苯丙素取代的酯型儿茶素（PSEC），MN 5含有重要的碱性化合物羟基肉桂酰儿茶素（HCCs）。因此，分离到一个新的PSEC（1，PSEC 636），它可以进一步在14个绿色茶样品中检测到。合成了一系列HCC（2-6），包括三种新的乙酰化HCC（3-5）。然后利用表面等离子体共振（SPR）技术分析了12种儿茶素与Mpro相互作用的平衡解离常数（KD）。PSEC 636（1）、EGC-C（2）和EC-CDA（3）的KD值分别为2.25、2.81和2.44 μM。此外，化合物1、2和3显示出潜在的Mpro抑制作用，IC 50分别为5.95 ± 0.17、9.09 ± 0.22和23.10 ± 0.69 μM。此外，我们使用诱导拟合对接（IFD），结合位姿代谢动力学（BPMD）和分子动力学（MD）来探索Mpro-1的稳定结合位姿，表明1可以与氨基酸残基THR 26，HIS 41，CYS 44，TYR 54，GLU 166和ASP 187紧密结合。计算机模拟研究表明，酯基、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，并可能被开发为抗COVID-19的治疗药物。
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.
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影响因子：
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