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

SARS-CoV-2 M (Mpro) is the critical cysteine protease in coronavirus viral replication. Tea polyphenols are effective M 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 (K ) for the interaction of 12 catechins and M . The K 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 M inhibition with IC 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 M -1, showing that 1 could tightly bond with the amino acid residues THR , HIS , CYS , TYR , GLU , and ASP . The computer modeling studies reveal that the ester, acetyl, and pyrogallol groups could improve inhibitory activity. Our research suggests that these catechins are effective M inhibitors, and might be developed as therapeutics against COVID-19.