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In silico studies of anti-oxidative and hot temperament-based phytochemicals as natural inhibitors of SARS-CoV-2 Mpro

Naderi Beni et al., PLOS ONE, doi:10.1371/journal.pone.0295014
Nov 2023  
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In Silico study showing potential benefits of the phytochemicals curcumin, savinin, and betulinic acid as an inhibitor of the SARS-CoV-2 main protease (Mpro). Molecular docking analysis revealed these hot temperament, antioxidant compounds bind strongly to both monomeric and dimeric forms of Mpro, with the higest predicted binding affinity for betulinic acid. MD simulations confirmed curcumin forms multiple hydrogen bonds with active site residues. MM-PBSA calculations also showed favorable binding free energy for the curcumin-Mpro complex. Additionally, ADMET analysis revealed curcumin satisfies criteria for drug-likeness. By targeting the viral protease, curcumin may inhibit SARS-CoV-2 replication.
In Silico studies predict inhibition of SARS-CoV-2 with curcumin or metabolites via binding to the spike Note A, Nag, Moschovou, Kandeil, Singh (B) (and specifically the receptor binding domain Note B, Kant, Srivastava, Eleraky), Mpro Note C, Moschovou, Kandeil, Srivastava, Naderi Beni, Rajagopal, Rampogu, Sekiou, Singh, Winih Kinasih, Thapa, Bahun, Eleraky, RNA-dependent RNA polymerase Note D, Singh (C), Eleraky, ACE2 Note E, Singh (B), Thapa, Alkafaas, nucleocapsid Note F, Hidayah, Suravajhala, and nsp10 Note G, Suravajhala proteins. In Vitro studies demonstrate inhibition of the spike Note A, Mohd Abd Razak (and specifically the receptor binding domain Note B, Goc (B)), Mpro Note C, Bahun, Guijarro-Real, Mohd Abd Razak, Wu, ACE2 Note E, Goc (B), and TMPRSS2 Note H, Goc (B) proteins. In Vitro studies demonstrate efficacy in Calu-3 Note I, Bormann, A549 Note J, Mohd Abd Razak, 293T Note K, Zhang, HEK293-hACE2 Note L, Nittayananta, Wu, 293T/hACE2/TMPRSS2 Note M, Septisetyani, and Vero E6 Note N, Bormann, Eleraky, Kandeil, Leka, Mohd Abd Razak, Nittayananta, Singh, Teshima, Marín-Palma cells. Curcumin is predicted to inhibit the interaction between the SARS-CoV-2 spike protein receptor binding domain and the human ACE2 receptor for the delta and omicron variants Kant, decreases pro-inflammatory cytokines induced by SARS-CoV-2 in peripheral blood mononuclear cells Marín-Palma, and alleviates SARS-CoV-2 spike protein-induced mitochondrial membrane damage and oxidative stress Zhang.
Naderi Beni et al., 30 Nov 2023, peer-reviewed, 4 authors. Contact:,
In Silico studies are an important part of preclinical research, however results may be very different in vivo.
This PaperCurcuminAll
In silico studies of anti-oxidative and hot temperament-based phytochemicals as natural inhibitors of SARS-CoV-2 Mpro
Ramin Naderi Beni, Parisa Elyasi-Ebli, Sajjad Gharaghani, Arefeh Seyedarabi
PLOS ONE, doi:10.1371/journal.pone.0295014
Main protease (M pro ) of SARS-CoV-2 is considered one of the key targets due to its role in viral replication. The use of traditional phytochemicals is an important part of complementary/alternative medicine, which also accompany the concept of temperament, where it has been shown that hot medicines cure cold and cold medicines cure hot, with cold and hot pattern being associated with oxidative and anti-oxidative properties in medicine, respectively. Molecular docking in this study has demonstrated that a number of anti-oxidative and hot temperament-based phytochemicals have high binding affinities to SARS-CoV-2 M pro , both in the monomeric and dimeric deposited states of the protein. The highest ranking phytochemicals identified in this study included savinin, betulinic acid and curcumin. Complexes of savinin, betulinic acid, curcumin as well as Nirmatrelvir (the only approved inhibitor, used for comparison) bound to SARS-CoV-2 M pro were further subjected to molecular dynamics simulations. Subsequently, RMSD, RMSF, Rg, number of hydrogen bonds, binding free energies and residue contributions (using MM-PBSA) and buried surface area (BSA), were analysed. The computational results suggested high binding affinities of savinin, betulinic acid and curcumin to both the monomeric and dimeric deposited states of M pro , while highlighting the lower binding energy of betulinic acid in comparison with savinin and curcumin and even Nirmatrelvir, leading to a greater stability of the betulinic acid-SARS-CoV-2 M pro complex. Overall, based on the increasing mutation rate in the spike protein and the fact that the SARS-CoV-2 M pro remains highly conserved, this study provides an insight into the use of phytochemicals against COVID-19 and other coronavirus diseases.
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