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Paradigm of Well-Orchestrated Pharmacokinetic Properties of Curcuminoids Relative to Conventional Drugs for the Inactivation of SARS-CoV-2 Receptors: An In Silico Approach

Srivastava et al., Stresses, doi:10.3390/stresses3030043
Aug 2023  
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In Silico analysis of curcuminoids showing similar drug-like properties and strong binding to the main protease and spike receptor binding domain proteins. Curcuminoid binding was comparable or better than existing drugs favipiravir, remdesivir, and HCQ. The results suggest curcuminoids, especially bisdemethoxycurcumin and curcumin, can disrupt viral proteins involved in replication and host cell attachment. Authors recommend research on combination therapy with other antivirals.
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), Boseila (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, Boseila, 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.
Srivastava et al., 30 Aug 2023, peer-reviewed, 6 authors. Contact: (corresponding author),,,,,
In Silico studies are an important part of preclinical research, however results may be very different in vivo.
This PaperCurcuminAll
Paradigm of Well-Orchestrated Pharmacokinetic Properties of Curcuminoids Relative to Conventional Drugs for the Inactivation of SARS-CoV-2 Receptors: An In Silico Approach
Akhileshwar Kumar Srivastava, Divya ; Singh, Priya ; Yadav, Monika ; Singh, Sandeep Kumar Singh, Ajay Kumar
Stresses, doi:10.3390/stresses3030043
To cure SARS-CoV-2 infection, the repurposing of conventional antiviral drugs is currently advocated by researchers, though their action is not very effective. The present study, based on in silico methods, was intended to increase the therapeutic potential of conventional drugs: hydroxychloroquine (HCQ), favipiravir (FAV), and remdesivir (REM) by using curcuminoids like curcumin (CUR), bisdemethoxycurcumin (BDMC), and demethoxycurcumin (DMC) as adjunct drugs against SARS-CoV-2 receptor proteins, namely main protease (Mpro) and the S1 receptor-binding domain (RBD). The curcuminoids exhibited similar pharmacokinetic properties to the conventional drugs. The webserver (ANCHOR) predicted greater protein stability for both receptors with a disordered score (<0.5). The molecular docking study showed that the binding energy was highest (-27.47 kcal/mol) for BDMC toward Mpro receptors, while the binding energy of CUR (-20.47 kcal/mol) and DMC (-20.58 kcal/mol) was lower than that of HCQ (-24.58 kcal/mol), FAV (-22.87 kcal/mol), and REM (-23.48 kcal/mol). In the case of S1-RBD, CUR had the highest binding energy (-38.84 kcal/mol) and the lowest was in FAV (-23.77 kcal/mol), whereas HCQ (-35.87 kcal/mol) and REM (-38.44 kcal/mol) had greater binding energy than BDMC (-28.07 kcal/mol) and DMC (-30.29 kcal/mol). Hence, this study envisages that these curcuminoids could be employed in combination therapy with conventional drugs to disrupt the stability of SARS-CoV-2 receptor proteins.
formation. Each result from FireDock provided a rank and scores based on the energy function. About 3.5 s was spent per candidate solution, which offers large-scale flexible refinement and the scoring of docking compounds to be performed. For the imaging of interactive molecules (antiviral drugs and curcuminoids) with SARS-CoV-2 receptors, a visualizer software, Discovery Studio 4.5 Client, was employed. Conclusions Various promising antiviral drugs against COVID-19 are being examined, although there have not yet been satisfactory outcomes. This study has focused on exploring the main causes of these drugs' ineffectiveness against the COVID-19 disease. Hence, the two receptor proteins, Mpro and S1-RBD, of SARS-CoV-2 were considered as targets for developing new drugs. The physicochemical properties (ADMET, BOILED-Egg construction, and target class) exhibited by curcuminoids (CUR, BDMC, and DMC) were similar to those of antiviral drugs such as HCQ, FAV, and REM. Rat acute toxicity LD50 of all the compounds was found to be in the low ranges between 2.1259 and 2.7169 mol/kg, indicating that curcuminoids can be investigated further by comparing them with conventional antiviral drugs. The protein disordered outcomes from ANCHOR gained scores of less than 0.5 for residues of Mpro and S1-RBD, indicating that these protein receptors have highly packed residues. Thus, it is relatively difficult to disturb the integrity of such viral proteins by employing a single drug. The binding..
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