scholarly journals Computational screening of FDA approved drugs of fungal origin that may interfere with SARS-CoV-2 spike protein activation, viral RNA replication, and post‐translational modification: a multiple target approach

2021 ◽  
Vol 9 (1) ◽  
Author(s):  
Rajveer Singh ◽  
Anupam Gautam ◽  
Shivani Chandel ◽  
Vipul Sharma ◽  
Arijit Ghosh ◽  
...  
Keyword(s):  
Rna Replication ◽  
Viral Rna ◽  
Spike Protein ◽  
Multiple Target ◽  
Post Translational Modification ◽  
Protein Activation ◽  
Computational Screening ◽  
Approved Drugs ◽  
Fda Approved Drugs

scholarly journals Mulberrofuran G, a Potent Inhibitor of SPIKE Protein of SARS Corona Virus 2

2021 ◽  
Author(s):  
Fatemeh Sadat Hosseini ◽  
Mohammad Reza Motamedi
Keyword(s):  
Molecular Docking ◽  
Virtual Screening ◽  
Active Site ◽  
Potential Role ◽  
Potent Inhibitor ◽  
Screening Method ◽  
Spike Protein ◽  
Treatment Agent ◽  
Approved Drugs ◽  
Fda Approved Drugs

Background: At the onset of the 2020 year, Coronavirus disease (COVID-19) has become a pandemic and infected many people worldwide. Despite all efforts, no cure was found for this infection. Bioinformatics and medicinal chemistry have a potential role in the primary consideration of drugs to treat this infection. With virtual screening and molecular docking, some potent compounds and medications can be found and modified and then applied to treat disease in the next steps. Methods: By virtual screening method and PRYX software, some Food and Drug Administration (FDA) approved drugs and natural compounds have been docked with the SPIKE protein of SARS-CoV-2. Some more potent agents have been selected, and then new structures are designed with better affinity than them. After that, we searched for the molecules with a similar structure to designed compounds to find the most potent compound to our target. Results: Because of the study of structures and affinities, mulberrofuran G was the most potent compound in this study. The compound has interacted strongly with residues in the probably active site of SPIKE. Conclusion: Mulberrofuran G can be a treatment agent candidate for COVID-19 because of its good affinity to SPIKE of the virus and inhibition of virus-cell adhesion and entrance.

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

2021 ◽  
Vol 2 (1) ◽  
pp. 16-27
Author(s):  
Zahra Sharifinia ◽  
◽  
Samira Asadi ◽  
Mahyar Irani ◽  
Abdollah Allahverdi ◽  
...  
Keyword(s):  
Virtual Screening ◽  
Angiotensin Converting Enzyme ◽  
Host Cells ◽  
Spike Protein ◽  
Potential Drug ◽  
Converting Enzyme ◽  
Angiotensin Converting Enzyme 2 ◽  
Approved Drugs ◽  
Fda Approved Drugs

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.

scholarly journals Repurposable Drugs for SARS-CoV-2 and Influenza Sepsis with scRNA-Seq Data Targeting Post-Transcription Modifications

2021 ◽  
Author(s):  
Zhihan Wang ◽  
Kai Guo ◽  
Pan Gao ◽  
Qinqin Pu ◽  
Changlong Li ◽  
...  
Keyword(s):  
Influenza A ◽  
Viral Infections ◽  
Human Life ◽  
Drug Repurposing ◽  
Post Translational Modification ◽  
Integrated Network ◽  
Ssrna Virus ◽  
Public Data ◽  
Approved Drugs ◽  
Fda Approved Drugs

Abstract Coronavirus disease 2019 (COVID-19) has been impacting almost every part of human life worldwide, posing a massive threat to human health. Due to the lack of time for new drug discovery and the urgent need for rapid disease control, drug repurposing presents a quick and effective alternative to finding therapeutics to reduce mortality. To identify potentially repurposable drugs, we employed a systematic approach to mine candidates from U.S. FDA-approved drugs and preclinical small-molecule compounds by integrating the gene expression perturbation data for chemicals from the Library of Integrated Network-Based Cellular Signatures project with a publicly available single-cell RNA sequencing dataset from mild and severe COVID-19 patients (GEO: GSE145926, public data available and accessed on April 22, 2020). We identified 281 FDA-approved drugs that have the potential to be effective against SARS-CoV-2 infection, 16 of which are currently undergoing clinical trials to evaluate their efficacy against COVID-19. We experimentally tested and demonstrated the inhibitory effects of tyrphostin-AG-1478 and brefeldin-a, two chemical inhibitors of glycosylation (a post-translational modification) on the replication of the single-stranded ribonucleic acid (ssRNA) virus influenza A virus as well as on the transcription and translation of host cell cytokines and their regulators (IFNs and ISGs). In conclusion, we have identified and experimentally validated repurposable anti-SARS-CoV-2 and IAV drugs using a systems biology approach, which may have the potential for treating these viral infections and their complications (sepsis).

scholarly journals Computational Screening of FDA Approved Drugs from ZINC Database for Potential Inhibitors of Zika Virus NS2B/NS3 Protease: A Molecular Docking and Dynamics Simulation Study

2021 ◽  
pp. 308-319
Author(s):  
Hasanain Abdulhameed Odhar ◽  
Salam Waheed Ahjel ◽  
Zanan Abdulhameed Odhar
Keyword(s):  
Molecular Docking ◽  
Virtual Screening ◽  
Zika Virus ◽  
Computational Study ◽  
Dynamics Simulation ◽  
Computational Screening ◽  
Approved Drugs ◽  
Ns3 Protease ◽  
Fda Approved Drugs ◽  
Molecular Docking And Dynamics

Zika virus is a mosquito borne pathogen with a single strand RNA genome. Human infection with this virus is usually asymptomatic, however outbreaks reported in both Pacific region and Latin America have been associated with increase in frequency of microcephaly in newborns and fetuses of infected mothers. Also, the incidence of Guillain-Barré syndrome had also increased among adults with Zika virus infection. Currently, neither vaccine nor antiviral drug has been developed against Zika virus. Structure based virtual screening can be employed, through drug repurposing strategy, to accelerate the identification of potential anti-Zika virus candidates. As such, virtual screening of approved drugs against Zika virus NS2B/NS3 protease can help to recognize new hits capable of hindering viral ability to replicate and evade immune system of the host. In this computational study, we have screened 1615 FDA approved drugs against NS2B/NS3 protease enzyme of Zika virus by using both molecular docking and dynamics simulation. Our virtual screening results indicate that the anti-muscarinic agent Darifenacin and the anti-diarrheal agent Loperamide may have a promising capacity to inhibit Zika virus NS2B/NS3 protease. According to molecular docking and dynamics simulation, these two approved drugs have good binding capacity to NS2B/NS3 as reported by docking energy of binding and MM-PBSA binding energy. In addition, both Darifenacin and Loperamide were able to maintain close proximity to protease crystal throughout simulation period. However, invitro evaluation of these two drugs against Zika virus NS2B/NS3 protease is required to confirm these computational results.

scholarly journals In Silico Identification of Widely Used and Well Tolerated Drugs That May Inhibit SARSCov- 2 3C-like Protease and Viral RNA-Dependent RNA Polymerase Activities, and May Have Potential to Be Directly Used in Clinical Trials

2020 ◽  
Author(s):  
Seref Gul ◽  
Onur Ozcan ◽  
sinan asar ◽  
Alper Okyar ◽  
Ibrahim Barıs ◽  
...  
Keyword(s):  
Rna Polymerase ◽  
In Silico ◽  
Cost Effective ◽  
Viral Rna ◽  
Rna Dependent Rna Polymerase ◽  
Docking Simulations ◽  
High Binding ◽  
Approved Drugs ◽  
Dynamics Simulations ◽  
Fda Approved Drugs

<p>Despite drastic strict measures, the spread of the SARS-CoV-2 is ongoing all around the world. There is no vaccine developed against this virus and no approved medication to be used for the treatment of COVID-2019. In this study, we performed <i>in silico</i> screening against two critical enzymes (3C-like protease (3CL<sup>pro</sup>) and viral RNA-dependent RNA polymerase (RdRp)), which play important roles in the SARS-CoV-2 life cycle, by using the U.S. Food and Drug Administration (FDA) approved drugs. Our docking simulations enable us to identify several hundred drugs that have high binding affinity for each target. To evaluate persistence of the drugs’ binding to each target near to physiological conditions we selected well tolerated and widely used ones for the molecular dynamics simulations. Simulations results revealed that following drugs were stably interacting with SARS-Cov-2 3CL<sup>pro</sup>: tetracycline and its derivatives, dihydroergotamine, ergotamine, dutasteride, nelfinavir, and paliperidone. A similar analysis with RdRp showed that eltrombopag, tipranavir, ergotamine, and conivaptan were bound with the enzyme during the simulation with high binding energy. Detailed analysis of docking results suggested that ergotamine, dihydroergotamine, bromocriptine, dutasteride, conivaptan, paliperidone, and tipranavir can bind to both enzymes with high affinity. Since these drugs are well tolerated, cost effective and widely used, our study suggested that they have potential to be used in clinical trial for the treatment of SARS-CoV-2 infected patients.</p>

scholarly journals The Binding mechanism of Ivermectin and levosalbutamol with spike protein of SARS-CoV-2

2021 ◽  
Author(s):  
Joyanta Kumar Saha ◽  
Md. Jahir Raihan
Keyword(s):  
Density Functional ◽  
Binding Energies ◽  
Spike Protein ◽  
Binding Mechanism ◽  
Functional Theory ◽  
Modeling Techniques ◽  
Charge Analysis ◽  
The Stability ◽  
Approved Drugs ◽  
Fda Approved Drugs

Abstract In this study, we have investigated the binding mechanism of two FDA approved drugs (ivermectin and levosalbutamol) with the spike protein of SARs-CoV-2 using three different computational modeling techniques. Molecular docking results predict that ivermectin shows a large binding affinity for spike protein (-9.0 kcal/mol) compared to levosalbutamol (-4.1 kcal/mol). Ivermectin binds with GLN492, GLN493, GLY496 and TRY505 residues in the spike protein through hydrogen bonds and levosalbutamol binds with TYR453 and TYR505 residues. Using density functional theory (DFT) studies, we have calculated the binding energies between ivermectin and levosalbutamol with residues in spike protein which favor their binding are − 17.8 kcal/mol and − 20.08 kcal/mol, respectively. The natural bond orbital (NBO) charge analysis has been performed to estimate the amount of charge transfer that occurred by two drugs during interaction with residues. Molecular dynamics (MD) study confirms the stability of spike protein bound with ivermectin through RMSD and RMSF analyses. Three different computer modeling techniques reveal that ivermectin is more stable than levosalbutamol in the active site of spike protein where hACE2 binds. Therefore, ivermectin can be a suitable inhibitor for SARS-CoV-2 to enter into the human cell through hACE2.

scholarly journals Potential SARS-CoV-2 Spike Protein-ACE2 Interface Inhibitors: Repurposing FDA-approved Drugs

2022 ◽  
Vol 000 (000) ◽  
pp. 000-000
Author(s):  
Valentina L. Kouznetsova ◽  
Aidan Zhang ◽  
Mark A. Miller ◽  
Mahidhar Tatineni ◽  
Jerry P. Greenberg ◽  
...  
Keyword(s):  
Spike Protein ◽  
Approved Drugs ◽  
Fda Approved Drugs

scholarly journals Drug repurposing for ligand-induced rearrangement of Sirt2 active site-based inhibitors via molecular modeling and quantum mechanics calculations

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Shiv Bharadwaj ◽  
Amit Dubey ◽  
Nitin Kumar Kamboj ◽  
Amaresh Kumar Sahoo ◽  
Sang Gu Kang ◽  
...  
Keyword(s):  
Simulation Analysis ◽  
Drug Repurposing ◽  
3D Qsar ◽  
Computational Screening ◽  
In Vitro Investigation ◽  
Qsar Models ◽  
Approved Drugs ◽  
Dynamics Simulations ◽  
Fda Approved Drugs

AbstractSirtuin 2 (Sirt2) nicotinamide adenine dinucleotide-dependent deacetylase enzyme has been reported to alter diverse biological functions in the cells and onset of diseases, including cancer, aging, and neurodegenerative diseases, which implicate the regulation of Sirt2 function as a potential drug target. Available Sirt2 inhibitors or modulators exhibit insufficient specificity and potency, and even partially contradictory Sirt2 effects were described for the available inhibitors. Herein, we applied computational screening and evaluation of FDA-approved drugs for highly selective modulation of Sirt2 activity via a unique inhibitory mechanism as reported earlier for SirReal2 inhibitor. Application of stringent molecular docking results in the identification of 48 FDA-approved drugs as selective putative inhibitors of Sirt2, but only top 10 drugs with docking scores > − 11 kcal/mol were considered in reference to SirReal2 inhibitor for computational analysis. The molecular dynamics simulations and post-simulation analysis of Sirt2-drug complexes revealed substantial stability for Fluphenazine and Nintedanib with Sirt2. Additionally, developed 3D-QSAR-models also support the inhibitory potential of drugs, which exclusively revealed highest activities for Nintedanib (pIC50 ≥ 5.90 µM). Conclusively, screened FDA-approved drugs were advocated as promising agents for Sirt2 inhibition and required in vitro investigation for Sirt2 targeted drug development.

scholarly journals In-silico identification of natural antiviral drug against SARS-CoV-2 and comparison with potential FDA approved drug targets

2020 ◽  
Vol 3 (4) ◽  
pp. 1-11
Author(s):  
SARRA AKERMI ◽  
Neha Lohar ◽  
Subrata Sinha ◽  
Surabhi Johari ◽  
Sunil Jayant ◽  
...  
Keyword(s):  
Free Energy ◽  
In Silico ◽  
High Throughput Screening ◽  
Drug Targets ◽  
Antiviral Drug ◽  
Spike Protein ◽  
Plant Metabolites ◽  
Secondary Plant Metabolites ◽  
Approved Drugs ◽  
Fda Approved Drugs

Antimalarial drugs Chloroquine and Hydroxychloroquine have garnered most attention recently as a successful remedy for COVID19. However, the use of these drugs is still questionable due to its undetermined efficacy and side effects. The present study utilizes in-silico high throughput screening of FDA approved antiviral compounds and secondary plant metabolites against spike protein of novel coronavirus (SARS-CoV-2). This target was chosen because it is instrumental in entry of virus into human cells. It is observed that the plant compound Tocopheryl-curcumin has more affinity for spike protein of SARS-CoV-2 in comparison to the majority of FDA approved drugs. Tocopheryl-curcumin binds with the binding site of RBD domain of spike protein (6VSB, chain A) with free energy (∆G) of binding of -11.20 kcal/mol and makes strong hydrogen bonds with amino acid residues of S366, V367, L368, S373, and K529. Among the FDA approved drugs, Pibrentasvir obtains top rank with free energy (∆G) of binding of -9.69 kcal/mol. whereas; surprisingly Chloroquine (-6.87 kcal/mol) and Hydroxychloroquine (-7.24 kcal/mol) ranked lower in our docking study. The toxicity prediction by VEGA predicts that tocopheryl-curcumin shows no toxicity as compared to FDA approved drugs. Therefore, we infer that the plant-based tocopheryl-curcumin could be considered as potential and safer drug against COVID 19 disease as compared to chemical based drugs.

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