Elsevier

Phytomedicine

Volume 96, February 2022, 153853
Phytomedicine

Discovery of Camellia sinensis catechins as SARS-CoV-2 3CL protease inhibitors through molecular docking, intra and extra cellular assays

https://doi.org/10.1016/j.phymed.2021.153853Get rights and content

Highlights

  • (-)-epicatechin 3-O-caffeoate shows strong intracellular 3CL protease inhibition.

  • (-)-epicatechin 3-O-caffeoate (EC-C) has a 3CL protease IC50 value at 1.58 µM.

  • EC-C, etc-pyrrolidinone C and D, and GCG have low KD values for 3CL protease binding.

  • Thr24, Thr26, Asn142, Gly143, His163, and Gln189 were the key amino acid residues for the interaction.

Abstract

Background and purpose

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.

Methods

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.

Results

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.

Conclusion

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.

Keywords

(–)-epicatechin 3-O-caffeoate
catechins
Camellia sinensis
SARS-CoV-2
ebselen

Abbreviations

3CLpro
3-chymotrypsin-like cysteine protease
CG
(+)-catechin gallate
ECG
(–)-epicatechin gallate
EGCG
(–)-epigallocatechin gallate
ETFs
ester-type flavoalkaloids
GCG
(+)-gallocatechin gallate
Flu
Fluminescence
IC50
half-maximal inhibitory concentration
KD
dissociation constants
Luc
Luciferase
RLU
Renilla luminescence
SARS-CoV
severe acute respiratory syndrome coronavirus
SPR
Surface plasmon resonance

Cited by (0)

1

Shi-Yu Liu and Wei Wang contributed equally to this work.

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