Dual inhibition of SARS-CoV-2 spike and main protease through a repurposed drug, rutin

Kumari, Anchala; Rajput, Vikrant Singh; Nagpal, Priya; Kukrety, Himanshi; Grover, Sonam; Grover, Abhinav

doi:10.1080/07391102.2020.1864476

Cited by 21 publications

(13 citation statements)

References 59 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…The root mean square deviation (RMSD) for Cα showed about 1 nm for whole residues and less than 0.2 nm for each domain in a chain of S protein regardless of mutant types (Table S1). These results were consistent with RMSD using whole residues within a chain in other research groups [28]. In order to identify conformational relationships among chains, V503 residues were confirmed as having the closest distance among the RBDs of chains in closed form (PDB ID 6VXX), with trimeric symmetry (Figure 1a) in whole trimeric S proteins.…”

Section: Distance Analysis Of V503 and N501 Residues Among Trimeric S Protein Protomerssupporting

confidence: 87%

Molecular Dynamics Studies on the Structural Characteristics for the Stability Prediction of SARS-CoV-2

Choi

Kim

Rhee

et al. 2021

IJMS

View full text Add to dashboard Cite

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) affects the COVID-19 pandemic in the world. The spike protein of the various proteins encoded in SARS-CoV-2 binds to human ACE2, fuses, and enters human cells in the respiratory system. Spike protein, however, is highly variable, and many variants were identified continuously. In this study, Korean mutants for spike protein (D614G and D614A-C terminal domain, L455F and F456L-RBD, and Q787H-S2 domain) were investigated in patients. Because RBD in spike protein is related to direct interaction with ACE2, almost all researches were focused on the RBD region or ACE2-free whole domain region. The 3D structure for spike protein complexed with ACE2 was recently released. The stability analysis through RBD distance among each spike protein chain and the binding free energy calculation between spike protein and ACE2 were performed using MD simulation depending on mutant types in 1-, 2-, and 3-open-complex forms. D614G mutant of CT2 domain, showing to be the most prevalent in the global pandemic, showed higher stability in all open-complex forms than the wild type and other mutants. We hope this study will provide an insight into the importance of conformational fluctuation in the whole domain, although RBD is involved in the direct interaction with ACE2.

show abstract

Section: Distance Analysis Of V503 and N501 Residues Among Trimeric S Protein Protomerssupporting

confidence: 87%

Molecular Dynamics Studies on the Structural Characteristics for the Stability Prediction of SARS-CoV-2

Choi

Kim

Rhee

et al. 2021

IJMS

View full text Add to dashboard Cite

show abstract

“…To the best of our knowledge, and with the notable exception of our previous work on quercetin [14], former predictions were based solely on computational analyses. They included molecular docking [55][56][57], with additional insights from both classical [58,59] and more advanced MD methods [60], or machine learning approaches [57]. In some cases, the compounds identified were further examined [56,61] in terms of their quantitative structure-activity relationship (QSAR) and expected pharmacokinetics properties including absorption, distribution, metabolism, excretion, and toxicity (ADMET).…”

Section: Discussionmentioning

confidence: 99%

Rutin Is a Low Micromolar Inhibitor of SARS-CoV-2 Main Protease 3CLpro: Implications for Drug Design of Quercetin Analogs

et al. 2021

View full text Add to dashboard Cite

The pandemic, due to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has stimulated the search for antivirals to tackle COVID-19 infection. Molecules with known pharmacokinetics and already approved for human use have been demonstrated or predicted to be suitable to be used either directly or as a base for a scaffold-based drug design. Among these substances, quercetin is known to be a potent in vitro inhibitor of 3CLpro, the SARS-CoV-2 main protease. However, its low in vivo bioavailability calls for modifications to its molecular structure. In this work, this issue is addressed by using rutin, a natural flavonoid that is the most common glycosylated conjugate of quercetin, as a model. Combining experimental (spectroscopy and calorimetry) and simulation techniques (docking and molecular dynamics simulations), we demonstrate that the sugar adduct does not hamper rutin binding to 3CLpro, and the conjugated compound preserves a high potency (inhibition constant in the low micromolar range, Ki = 11 μM). Although showing a disruption of the pseudo-symmetry in the chemical structure, a larger steric volume and molecular weight, and a higher solubility compared to quercetin, rutin is able to associate in the active site of 3CLpro, interacting with the catalytic dyad (His41/Cys145). The overall results have implications in the drug-design of quercetin analogs, and possibly other antivirals, to target the catalytic site of the SARS-CoV-2 3CLpro.

show abstract

“…The protein structure used for the molecular docking and simulation studies is shown in Figure 2. The binding pocket volume and surface area were determined through the CASTp webserver, utilizing previous findings [24]. A binding pocket was predicted at the surface as well as in the interior of proteins.…”

Section: Structural Analysismentioning

confidence: 99%

In Silico Identification and Validation of Organic Triazole Based Ligands as Potential Inhibitory Drug Compounds of SARS-CoV-2 Main Protease

2021

View full text Add to dashboard Cite

The SARS-CoV-2 virus is highly contagious to humans and has caused a pandemic of global proportions. Despite worldwide research efforts, efficient targeted therapies against the virus are still lacking. With the ready availability of the macromolecular structures of coronavirus and its known variants, the search for anti-SARS-CoV-2 therapeutics through in silico analysis has become a highly promising field of research. In this study, we investigate the inhibiting potentialities of triazole-based compounds against the SARS-CoV-2 main protease (Mpro). The SARS-CoV-2 main protease (Mpro) is known to play a prominent role in the processing of polyproteins that are translated from the viral RNA. Compounds were pre-screened from 171 candidates (collected from the DrugBank database). The results showed that four candidates (Bemcentinib, Bisoctrizole, PYIITM, and NIPFC) had high binding affinity values and had the potential to interrupt the main protease (Mpro) activities of the SARS-CoV-2 virus. The pharmacokinetic parameters of these candidates were assessed and through molecular dynamic (MD) simulation their stability, interaction, and conformation were analyzed. In summary, this study identified the most suitable compounds for targeting Mpro, and we recommend using these compounds as potential drug molecules against SARS-CoV-2 after follow up studies.

show abstract

Dual inhibition of SARS-CoV-2 spike and main protease through a repurposed drug, rutin

Cited by 21 publications

References 59 publications

Molecular Dynamics Studies on the Structural Characteristics for the Stability Prediction of SARS-CoV-2

Molecular Dynamics Studies on the Structural Characteristics for the Stability Prediction of SARS-CoV-2

Rutin Is a Low Micromolar Inhibitor of SARS-CoV-2 Main Protease 3CLpro: Implications for Drug Design of Quercetin Analogs

In Silico Identification and Validation of Organic Triazole Based Ligands as Potential Inhibitory Drug Compounds of SARS-CoV-2 Main Protease

Contact Info

Product

Resources

About