Drug Repurposing to Identify Therapeutics Against COVID 19 with SARS-Cov-2 Spike Glycoprotein and Main Protease as Targets: An in Silico Study

Kumar, Arun; Sharanya, S.; Abhithaj, J; Sadasivan, C.

doi:10.26434/chemrxiv.12090408.v1

Cited by 4 publications

(2 citation statements)

References 11 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Gemcitabine and cidofovir were reported to inhibit SARS-CoV and SARS-CoV-2 proteins with IC 50 values of 4.95 µM and 36 µM [54,55]. Further, telbivudine, tipiracil, cytarabine, and citicoline were recommended as 3CL pro inhibitors [56][57][58][59][60][61]. This transitory literature scanning confirms these pharmaceuticals' activity against 3CL pro of SARS-CoV-2, as demonstrated in the present study.…”

Section: The Binding Free Energiessupporting

confidence: 86%

Molecular Docking and Dynamics Investigations for Identifying Potential Inhibitors of the 3-Chymotrypsin-like Protease of SARS-CoV-2: Repurposing of Approved Pyrimidonic Pharmaceuticals for COVID-19 Treatment

Elzupir

2021

Molecules

View full text Add to dashboard Cite

This study demonstrates the inhibitory effect of 42 pyrimidonic pharmaceuticals (PPs) on the 3-chymotrypsin-like protease of SARS-CoV-2 (3CLpro) through molecular docking, molecular dynamics simulations, and free binding energies by means of molecular mechanics–Poisson Boltzmann surface area (MM-PBSA) and molecular mechanics–generalized Born surface area (MM-GBSA). Of these tested PPs, 11 drugs approved by the US Food and Drug Administration showed an excellent binding affinity to the catalytic residues of 3CLpro of His41 and Cys145: uracil mustard, cytarabine, floxuridine, trifluridine, stavudine, lamivudine, zalcitabine, telbivudine, tipiracil, citicoline, and uridine triacetate. Their percentage of residues involved in binding at the active sites ranged from 56 to 100, and their binding affinities were in the range from −4.6 ± 0.14 to −7.0 ± 0.19 kcal/mol. The molecular dynamics as determined by a 200 ns simulation run of solvated docked complexes confirmed the stability of PP conformations that bound to the catalytic dyad and the active sites of 3CLpro. The free energy of binding also demonstrates the stability of the PP–3CLpro complexes. Citicoline and uridine triacetate showed free binding energies of −25.53 and −7.07 kcal/mol, respectively. Therefore, I recommend that they be repurposed for the fight against COVID-19, following proper experimental and clinical validation.

show abstract

Section: The Binding Free Energiessupporting

confidence: 86%

Molecular Docking and Dynamics Investigations for Identifying Potential Inhibitors of the 3-Chymotrypsin-like Protease of SARS-CoV-2: Repurposing of Approved Pyrimidonic Pharmaceuticals for COVID-19 Treatment

Elzupir

2021

Molecules

View full text Add to dashboard Cite

show abstract

“…Through in silico studies, Folic acid was capable to bind to the active site of SARS-CoV-2 main protease efficiently [25]. In addition, several computational docking studies indicated that Levomefolic acid has the potential to avoid the binding of Spike protein of SARS-CoV-2 to human ACE2 receptor and then COVID 19 infection [26]. Comparing to our study, Levomefolic acid has interaction with important residues of S1 domain of Spike protein including Glu 406, Ile 418, Lys 417, Tyr 453 with a lower affinity score of -5.3 kcal/mol.…”

Section: Discussionmentioning

confidence: 99%

Virtual screening as therapeutic strategy of COVID-19 targeting angiotensin-converting enzyme 2

et al. 2021

View full text Add to dashboard Cite

Objective: The receptor-binding domain (RBD) of the S1 domain of the SARS-CoV- 2 Spike protein performs a key role in the interaction with Angiotensin-converting enzyme 2 (ACE2), leading to both subsequent S2 domain-mediated membrane fusion and incorporation of viral RNA in host cells. Methods: In this study, we investigated the inhibitor’s targeted compounds through existing human ACE2 drugs to use as a future viral invasion. 54 FDA approved drugs were selected to assess their binding affinity to the ACE2 receptor. The structurebased methods via computational ones have been used for virtual screening of the best drugs from the drug database. Key Findings: The ligands “Cinacalcet” and “Levomefolic acid” highaffinity scores can be a potential drug preventing Spike protein of SARS-CoV-2 and human ACE2 interaction. Levomefolic acid from vitamin B family was proved to be a potential drug as a spike protein inhibitor in previous clinical and computational studies. Besides that, in this study, the capability of Levomefolic acid to avoid ACE2 and Spike protein of SARS-CoV-2 interaction is indicated. Therefore, it is worth to consider this drug for more in vitro investigations as ACE2 and Spike protein inhibition candidate. Conclusion: The two Cinacalcet and Levomefolic acid are the two ligands that have highest energy binding for human ACE2 blocking among 54 FDA approved drugs.

show abstract

Identification of SARS-CoV-2 induced pathways reveal drug repurposing strategies

Han

Hwang

Tzelepis

et al. 2020

Preprint

View full text Add to dashboard Cite

The global outbreak of SARS-CoV-2 necessitates the rapid development of new therapies against COVID-19 infection. Here, we present the identification of 200 approved drugs, appropriate for repurposing against COVID-19. We constructed a SARS-CoV-2-induced protein (SIP) network, based on disease signatures defined by COVID-19 multi-omic datasets(Bojkova et al., 2020; Gordon et al., 2020), and cross-examined these pathways against approved drugs. This analysis identified 200 drugs predicted to target SARS-CoV-2-induced pathways, 40 of which are already in COVID-19 clinical trials(Clinicaltrials.gov, 2020) testifying to the validity of the approach. Using artificial neural network analysis we classified these 200 drugs into 9 distinct pathways, within two overarching mechanisms of action (MoAs): viral replication (130) and immune response (70). A subset of drugs implicated in viral replication were tested in cellular assays and two (proguanil and sulfasalazine) were shown to inhibit replication. This unbiased and validated analysis opens new avenues for the rapid repurposing of approved drugs into clinical trials.

show abstract

Drug Repurposing to Identify Therapeutics Against COVID 19 with SARS-Cov-2 Spike Glycoprotein and Main Protease as Targets: An in Silico Study

Cited by 4 publications

References 11 publications

Molecular Docking and Dynamics Investigations for Identifying Potential Inhibitors of the 3-Chymotrypsin-like Protease of SARS-CoV-2: Repurposing of Approved Pyrimidonic Pharmaceuticals for COVID-19 Treatment

Molecular Docking and Dynamics Investigations for Identifying Potential Inhibitors of the 3-Chymotrypsin-like Protease of SARS-CoV-2: Repurposing of Approved Pyrimidonic Pharmaceuticals for COVID-19 Treatment

Virtual screening as therapeutic strategy of COVID-19 targeting angiotensin-converting enzyme 2

Identification of SARS-CoV-2 induced pathways reveal drug repurposing strategies

Contact Info

Product

Resources

About