A Multi-Pronged Approach Targeting SARS-CoV-2 Proteins Using Ultra-Large Virtual Screening

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), previously known as 2019 novel coronavirus (2019-nCoV), has spread rapidly across the globe, creating an unparalleled global health burden and spurring a deepening economic crisis. As of July 7th, 2020, almost seven months into the outbreak, there are no approved vaccines and few treatments available. Developing drugs that target multiple points in the viral life cycle could serve as a strategy to tackle the current as well as future coronavirus pandemics. Here we leverage the power of our recently developed in silico screening platform, VirtualFlow, to identify inhibitors that target SARS-CoV-2. VirtualFlow is able to efficiently harness the power of computing clusters and cloud-based computing platforms to carry out ultra-large scale virtual screens. In this unprecedented structure-based multi-target virtual screening campaign, we have used VirtualFlow to screen an average of approximately 1 billion molecules against each of 40 different target sites on 17 different potential viral and host targets in the cloud. In addition to targeting the active sites of viral enzymes, we also target critical auxiliary sites such as functionally important protein-protein interaction interfaces. This multi-target approach not only increases the likelihood of finding a potent inhibitor, but could also help identify a collection of anti-coronavirus drugs that would retain efficacy in the face of viral mutation. Drugs belonging to different regimen classes could be combined to develop possible combination therapies, and top hits that bind at highly conserved sites would be potential candidates for further development as coronavirus drugs. Here, we present the top 200 in silico hits for each target site. While in-house experimental validation of some of these compounds is currently underway, we want to make this array of potential inhibitor candidates available to researchers worldwide in consideration of the pressing need for fast-tracked drug development.

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Virtual screening for small-molecule inhibitors of PD-1/PD-L1 protein-protein interaction using in silico fragment mapping method

SDRP Journal of Computational Chemistry & Molecular Modelling ◽

10.25177/jccmm.3.1.1 ◽

2019 ◽

Vol 3 (1) ◽

pp. 1-10 ◽

Cited By ~ 3

Author(s):

Yusuke Sako ◽

Shuichi Hirono ◽

Noriyuki Yamaotsu

Keyword(s):

Virtual Screening ◽

Small Molecule ◽

Protein Interaction ◽

In Silico ◽

Small Molecule Inhibitors ◽

Mapping Method ◽

Protein Protein Interaction ◽

L1 Protein

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Identification of inhibitors of Bcl-2 family protein-protein interaction by combining the BRET screening platform with virtual screening

Biochemical and Biophysical Research Communications ◽

10.1016/j.bbrc.2020.05.045 ◽

2020 ◽

Vol 527 (3) ◽

pp. 709-715 ◽

Cited By ~ 1

Author(s):

I-Seul Park ◽

Haeng Ran Seo ◽

Kideok Kim ◽

Honggun Lee ◽

David Shum ◽

...

Keyword(s):

Virtual Screening ◽

Protein Interaction ◽

Protein Protein Interaction ◽

Family Protein ◽

Screening Platform

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Non-covalent TMPRSS2 inhibitors identified from virtual screening

10.1101/2020.12.28.424413 ◽

2020 ◽

Author(s):

Xin Hu ◽

Jonathan H. Shrimp ◽

Hui Guo ◽

Alexey Zakharov ◽

Sankalp Jain ◽

...

Keyword(s):

Life Cycle ◽

Virtual Screening ◽

Membrane Fusion ◽

Large Scale ◽

Spike Protein ◽

Binding Model ◽

Drug Candidates ◽

Database Screening ◽

Further Development ◽

Significant Attention

AbstractThe SARS-CoV-2 pandemic has prompted researchers to pivot their efforts to finding anti-viral compounds and vaccines. In this study, we focused on the human host cell transmembrane protease serine 2 (TMPRSS2), which plays an important role in the viral life cycle by cleaving the spike protein to initiate membrane fusion. TMPRSS2 is an attractive target and has received significant attention for the development of drugs against SARS and MERS. Starting with comparative structural modeling and binding model analysis, we developed an efficient pharmacophore-based approach and applied in a large-scale in silico database screening for small molecule inhibitors against TMPRSS2. A number of novel inhibitors were identified, providing starting points for further development of drug candidates for the treatment of COVID-19.

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In Silico Study of Pubchem Compounds for Solanum torvum as Antiviral Agent against SARS-CoV-2

The Open COVID Journal ◽

10.2174/2666958702101010235 ◽

2021 ◽

Vol 1 (1) ◽

pp. 235-242

Author(s):

Subramaniyan Vaithilingam ◽

Lakshmipathy Vivekanandan ◽

Moorthy S. Krishna

Keyword(s):

In Silico ◽

Active Sites ◽

Treatment Options ◽

3D Structure ◽

Antiviral Agent ◽

Ligand Docking ◽

Solanum Torvum ◽

Ligand Interaction ◽

Pubchem Database ◽

Novel Coronavirus

Background: The recent epidemic outbreak of a novel coronavirus called SARS-CoV-2 has caused suffering among many people in the form of respiratory tract infection. Currently, there are no targeted drugs, and effective treatment options remain limited. Objective: In order to rapidly discover new compounds for clinical purposes, in silico drug design and virtual drug screening have been initiated to identify new drug leads that target the main protease of the COVID-19 virus. Mpro is a key CoV enzyme, which plays a pivotal role in mediating viral replication and transcription, making it an attractive drug target for this virus. Methods: The present study was done to investigate the PubChem compounds of an ayurvedic herb Solanum torvum as an effective antiviral agent against COVID-19. The PubChem compounds like Torvoside H, Torvoside A, Torvoside E, Torvoside F, Torvonin A, 2,3,4-trimethyltriacontane, Torvanol A Q27134802, 5-hexatriacontanone, Jurubine, Tritriacontan-3-one, Torvanol A, Chlorogenone Spirostane-3,6-dione of Solanum torvum were downloaded from NCBI PubChem database acting as ligands for protein ligand docking. The 3D structure of the viral MPro (PDB ID: 6yb7) was retrieved from the RCSB PDB database. The active sites and binding sites were analyzed, and Docking molecular simulations were realized among a total of 12 ligands against COVID-19. Results: The PubChem compounds from the fruits of Solanum torvum showed good docking score and protein-ligand interaction, indicating that the PubChem compounds can cure the COVID-19 disease and act as an effective antiviral agent. Conclusion: Most of the PubChem compounds in the fruits of Solanum torvum showed better paramagnetic parameters.

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Virtual Screening and In Silico Interactions Studies for Potential Antivirals and Diagnostics against the Spike protein from the Novel Coronavirus SARS-Cov-2

IOP Conference Series Materials Science and Engineering ◽

10.1088/1757-899x/1192/1/012025 ◽

2021 ◽

Vol 1192 (1) ◽

pp. 012025

Author(s):

F I Che Abd Aziz ◽

F A Ahmad Fuad ◽

S Tanbin

Keyword(s):

Monoclonal Antibodies ◽

Binding Energy ◽

Virtual Screening ◽

Spike Protein ◽

Protein Protein Interaction ◽

Entry Pathway ◽

Therapeutic Drugs ◽

Global Pandemic ◽

Potential Spike ◽

Novel Coronavirus

Abstract COVID-19 is a newly-emerged respiratory disease that is caused by the SARS-CoV-2, the seventh known Coronaviruses strain that has struck a global pandemic. The sharp increase in the number of positive cases worldwide necessitates highly-sensitive diagnostics kits and effective antiviral drugs to be developed for the populations. One of the antigens that is targeted for antibody neutralisation is the coronavirus Spike protein that consists of the S1 and S2 subunits, which mediated the entry pathway into the host’s cell. Thus, the Spike protein has been suggested as a potential target for Covid-19 diagnostics and drug design. This study aims to evaluate the interactions between the SARS-CoV-2 Spike protein and the known monoclonal antibodies from Coronaviruses and to screen for potential Spike protein inhibitors. Virtual screening was conducted based on two compounds, N‐acetyl‐D‐glucosamine (NAG) and Hesperetin, which is a small molecule that binds to the SARS-CoV-2 Spike protein structure and a natural compound that has prophylactic agents against SARS-CoV-2 infection as it binds to Spike protein, respectively. Protein-protein interaction studies were conducted by using the STRING webserver, prior to performing rigid docking using SWISSDOCK and visualised using USCF Chimera. Meanwhile, ligand-based screening was conducted through Ultrafast Shape Recognition Virtual Screening Database (USR-VS), and structure-based screening was performed via AutoDock4 software. The toxicity of the compounds was predicted using ProTox-II database. Possible interactions have been observed between the known monoclonal antibodies with the SARS-CoV-2 Spike protein, where M396 monoclonal antibody has shown the strongest interaction with a binding energy of -8.50 kcal/mol. Meanwhile, virtual screening has yielded several compounds that indicate the possibility to inhibit the SARS-CoV-2 Spike protein, where Tamarixetin has shown the strongest binding energy of -7.93 kcal/mol. These findings have potentials to be further evaluated in the future for the development of improved diagnostic kits and potential therapeutic drugs that specifically target the Spike protein of SARS-CoV-2.

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Encroaching genomics: adapting large-scale science to small academic laboratories

Physiological Genomics ◽

10.1152/physiolgenomics.2000.2.3.85 ◽

2000 ◽

Vol 2 (3) ◽

pp. 85-92

Author(s):

MARGRET B. EINARSON ◽

ERICA A. GOLEMIS

Keyword(s):

Large Scale ◽

Biological Research ◽

Public Attention ◽

Protein Protein Interaction ◽

Genome Wide ◽

Genomic Consortium ◽

The Face ◽

Multiple Species ◽

The Impact

Einarson, Margret B., and Erica A. Golemis. Encroaching genomics: adapting large-scale science to small academic laboratories. Physiol Genomics 2: 85–92, 2000.—The process of conducting biological research is undergoing a profound metamorphosis due to the technological innovations and torrent of information resulting from the execution of multiple species genome projects. The further tasks of mapping polymorphisms and characterizing genome-wide protein-protein interaction (the characterization of the proteome) will continue to garner resources, talent, and public attention. Although some elements of these whole genome size projects can only be addressed by large research groups, consortia, or industry, the impact of these projects has already begun to transform the process of research in many small laboratories. Although the impact of this transformation is generally positive, laboratories engaged in types of research destined to be dominated by the efforts of a genomic consortium may be negatively impacted if they cannot rapidly adjust strategies in the face of new large-scale competition. The focus of this report is to outline a series of strategies that have been productively utilized by a number of small academic laboratories that have attempted to integrate such genomic resources into research plans with the goal of developing novel physiological insights.

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Inhibition of SARS-CoV-2 main protease by phenolic compounds from Manilkara hexandra (Roxb.) Dubard assisted by metabolite profiling and in silico virtual screening

RSC Advances ◽

10.1039/d0ra05679k ◽

2020 ◽

Vol 10 (53) ◽

pp. 32148-32155 ◽

Cited By ~ 1

Author(s):

Fatma M. Abd El-Mordy ◽

Mohamed M. El-Hamouly ◽

Magda T. Ibrahim ◽

Gehad Abd El-Rheem ◽

Omar M. Aly ◽

...

Keyword(s):

Phenolic Compounds ◽

Virtual Screening ◽

In Silico ◽

Metabolite Profiling ◽

Main Protease ◽

Novel Coronavirus

SARS-CoV-2 is a novel coronavirus that was first identified during the outbreak in Wuhan, China in 2019.

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Dose COVID-19 Uncovered a New Feature of Metronidazole Drug?

10.26434/chemrxiv.12526277.v2 ◽

2020 ◽

Author(s):

Mohammad Seyedhamzeh ◽

Bahareh Farasati Far ◽

Mehdi Shafiee Ardestani ◽

Shahrzad Javanshir ◽

Fatemeh Aliabadi ◽

...

Keyword(s):

Molecular Docking ◽

Drug Discovery ◽

Virtual Screening ◽

Active Sites ◽

Initial Plasma ◽

New Feature ◽

Metronidazole Benzoate ◽

Global Health Problem ◽

A Current ◽

Pro Inflammatory Cytokines

Studies of coronavirus disease 2019 (COVID-19) as a current global health problem shown the initial plasma levels of most pro-inflammatory cytokines increased during the infection, which leads to patient countless complications. Previous studies also demonstrated that the metronidazole (MTZ) administration reduced related cytokines and improved treatment in patients. However, the effect of this drug on cytokines has not been determined. In the present study, the interaction of MTZ with cytokines was investigated using molecular docking as one of the principal methods in drug discovery and design. According to the obtained results, the IL12-metronidazole complex is more stable than other cytokines, and an increase in the surface and volume leads to prevent to bind to receptors. Moreover, ligand-based virtual screening of several libraries showed metronidazole phosphate, metronidazole benzoate, 1-[1-(2-Hydroxyethyl)-5- nitroimidazol-2-yl]-N-methylmethanimine oxide, acyclovir, and tetrahydrobiopterin (THB or BH4) like MTZ by changing the surface and volume prevents binding IL-12 to the receptor. Finally, the inhibition of the active sites of IL-12 occurred by modifying the position of the methyl and hydroxyl functional groups in MTZ.

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Discovery of New AKT1 Inhibitors by Combination of In silico Structure Based Virtual Screening Approaches and Biological Evaluations

10.26434/chemrxiv.7591202 ◽

2019 ◽

Author(s):

Filip Fratev ◽

Denisse A. Gutierrez ◽

Renato J. Aguilera ◽

suman sirimulla

Keyword(s):

Virtual Screening ◽

Success Rate ◽

Protein Interactions ◽

In Silico ◽

Biological Data ◽

In Vitro Binding ◽

Vitro Binding ◽

Screening Protocol ◽

Screening Approaches

AKT1 is emerging as a useful target for treating cancer. Herein, we discovered a new set of ligands that inhibit the AKT1, as shown by in vitro binding and cell line studies, using a newly designed virtual screening protocol that combines structure-based pharmacophore and docking screens. Taking together with the biological data, the combination of structure based pharamcophore and docking methods demonstrated reasonable success rate in identifying new inhibitors (60-70%) proving the success of aforementioned approach. A detail analysis of the ligand-protein interactions was performed explaining observed activities.

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