Predictive modeling and therapeutic repurposing of natural compounds against the receptor-binding domain of SARS-CoV-2

Abstract Coronavirus disease (COVID-19) is caused by SARS-CoV-2 and represents the causative agent of a potentially lethal disease. COVID-19 has been described as a significant global public health pandemic by the World Health Organization due to its high mortality rate, rapid spread, and the lack of drugs and vaccines for it. Active antiviral drugs are desperately needed to combat the potential return of severe acute respiratory syndrome (SARS).In this study, we selected 39 natural compounds present in plants, algae, and sponges with antiviral activity. Molecular docking was used to screen the compounds’ activity on SARS- CoV-2 RNA-dependent-RNA polymerase, receptor-binding domain (RBD), and the human ACE2 receptor. Compounds with binding energy ≤ -6.5 kcal/mol enter pre-clinical testing using in silco ADME/Tox (absorption, distribution, metabolism, excretion, and toxicity).We found eight potential SARS-CoV-2 inhibitors: (glycyrrhizin, rutin, baicalin, 1, 6-di-O- galloyl-beta-D-glucose, pyropheophorbide A, pheophorbide A, beta-Sitosterol, and vitexin). These outcomes indicate that these compounds could be potential candidates to be utilized in lead optimization for the design and production of the anti-SARS-CoV-2 drug.

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Virtual Screening of Anti-Viral Drugs and Natural Compounds for Potential Inhibition of the Novel SARS-Cov-2 Spike Receptor-Binding Domain

University of the Future: Re-Imagining Research and Higher Education ◽

10.29117/quarfe.2020.0281 ◽

2020 ◽

Author(s):

Shilu M. Mathew ◽

Fatiha Benslimane ◽

Asmaa A. Althani ◽

Hadi M. Yassine

Keyword(s):

Receptor Binding ◽

Protein Structures ◽

Natural Compounds ◽

Binding Domain ◽

Host Cells ◽

Receptor Binding Domain ◽

Binding Modes ◽

S Protein ◽

Computational Screening ◽

Natural Drugs

Background: The spike (S) protein of SARS-CoV-2 harbors the receptor-binding domain (RBD) that mediates the virus's entry to host cells. The aim of this study was to identify novel inhibitors that target the RBD domain of S-protein through computational screening of chemical and natural compounds. Method: The S protein was modelled from the recently resolved and the previously described SARS-CoV protein structures. CLC Drug Discovery was used to computationally screen for potential inhibitory effects of currently prescribed drugs (n= 22) anti-viral natural drugs (n=100), natural compounds (n= 35032). QSAR was also performed. Results: Among currently precribed drugs to treat SARS-CoV2, hydroxychloroquine and favipiravir were identified as the best binders with an average of 4Hbonds, the binding affinity (BA): -36.66 kcal·mol−1, and interaction energy (IE): -6.63 kcal·mol−1. After the evaluation of anti-viral compounds, fosamprenavir and abacavir showed effective binding of 5H-bonds, with average BA: -18.75 kcal·mol−1, and IE: -3.57 kcal·mol−1. Furthermore, screening of 100 natural anti-viral compounds predicted potential binding modes of glycyrrhizin, nepritin, punicalagin, EGCG, and theaflavin (average BA: -49.88 kcal·mol−1, and IE: -4.35 kcal·mol−1). Additionally, the study reports 25 natural compounds that showed effective binding with an improved average BA: 51.46 kcal·mol−1. Conclusion: Using computational screening, we identified potential SARSCoV-2 spike inhibitors that bind to the RBD region.

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Inhibition Ability of Natural Compounds on Receptor-Binding Domain of SARS-CoV2: An In Silico Approach

Pharmaceuticals ◽

10.3390/ph14121328 ◽

2021 ◽

Vol 14 (12) ◽

pp. 1328

Author(s):

Miroslava Nedyalkova ◽

Mahdi Vasighi ◽

Subrahmanyam Sappati ◽

Anmol Kumar ◽

Sergio Madurga ◽

...

Keyword(s):

Machine Learning ◽

Molecular Docking ◽

Binding Affinity ◽

Receptor Binding ◽

In Silico ◽

Experimental Studies ◽

Natural Compounds ◽

Binding Domain ◽

Machine Learning Techniques ◽

Receptor Binding Domain

The lack of medication to treat COVID-19 is still an obstacle that needs to be addressed by all possible scientific approaches. It is essential to design newer drugs with varied approaches. A receptor-binding domain (RBD) is a key part of SARS-CoV-2 virus, located on its surface, that allows it to dock to ACE2 receptors present on human cells, which is followed by admission of virus into cells, and thus infection is triggered. Specific receptor-binding domains on the spike protein play a pivotal role in binding to the receptor. In this regard, the in silico method plays an important role, as it is more rapid and cost effective than the trial and error methods using experimental studies. A combination of virtual screening, molecular docking, molecular simulations and machine learning techniques are applied on a library of natural compounds to identify ligands that show significant binding affinity at the hydrophobic pocket of the RBD. A list of ligands with high binding affinity was obtained using molecular docking and molecular dynamics (MD) simulations for protein–ligand complexes. Machine learning (ML) classification schemes have been applied to obtain features of ligands and important descriptors, which help in identification of better binding ligands. A plethora of descriptors were used for training the self-organizing map algorithm. The model brings out descriptors important for protein–ligand interactions.

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Destabilizing the Structural Integrity of SARS-CoV2 Receptor Proteins by Curcumin Along with Hydroxychloroquine: An Insilco Approach for a Combination Therapy

10.26434/chemrxiv.12090438.v1 ◽

2020 ◽

Cited By ~ 1

Author(s):

Akhileshwar Srivastava ◽

Divya Singh

Keyword(s):

Binding Energy ◽

Combination Therapy ◽

Receptor Binding ◽

Structural Integrity ◽

Binding Domain ◽

Receptor Binding Domain ◽

Receptor Proteins ◽

Main Protease ◽

The Stability ◽

Therapeutic Activities

Presently, an emerging disease (COVID-19) has been spreading across the world due to coronavirus (SARS-CoV2). For treatment of SARS-CoV2 infection, currently hydroxychloroquine has been suggested by researchers, but it has not been found enough effective against this virus. The present study based on in silico approaches was designed to enhance the therapeutic activities of hydroxychloroquine by using curcumin as an adjunct drug against SARS-CoV2 receptor proteins: main-protease and S1 receptor binding domain (RBD). The webserver (ANCHOR) showed the higher protein stability for both receptors with disordered score (<0.5). The molecular docking analysis revealed that the binding energy (-24.58 kcal/mol) of hydroxychloroquine was higher than curcumin (-20.47 kcal/mol) for receptor main-protease, whereas binding energy of curcumin (<a>-38.84</a> kcal/mol) had greater than hydroxychloroquine<a> (-35.87</a> kcal/mol) in case of S1 receptor binding domain. Therefore, this study suggested that the curcumin could be used as combination therapy along with hydroxychloroquine for disrupting the stability of SARS-CoV2 receptor proteins

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Amoxicillin Trihydrate-Clavulanate Potassium As Potential Inhibitor of 2019 Novel Coronavirus Main Protease with Strong Receptor-Binding Domain (RBD), Molecular Docking and SAR Study

SSRN Electronic Journal ◽

10.2139/ssrn.3580230 ◽

2020 ◽

Author(s):

Khedidja benarous ◽

Talia Serseg ◽

Mohamed Yousfi

Keyword(s):

Molecular Docking ◽

Receptor Binding ◽

Binding Domain ◽

Receptor Binding Domain ◽

Potential Inhibitor ◽

Main Protease ◽

Amoxicillin Trihydrate ◽

Novel Coronavirus ◽

Sar Study

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Amoxicillin and Clavulanate as Potential Multiple Effect Inhibitors of 2019 Novel Coronavirus Main Protease and RNA-Dependent RNA Polymerase with Strong Receptor-Binding Domain (RBD), Molecular Docking and SAR Study

SSRN Electronic Journal ◽

10.2139/ssrn.3618303 ◽

2020 ◽

Author(s):

Khedidja benarous ◽

Talia Serseg ◽

Mohamed Yousfi

Keyword(s):

Molecular Docking ◽

Rna Polymerase ◽

Receptor Binding ◽

Binding Domain ◽

Receptor Binding Domain ◽

Rna Dependent Rna Polymerase ◽

Multiple Effect ◽

Main Protease ◽

Novel Coronavirus ◽

Sar Study

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Role of key point Mutations in Receptor Binding Domain of SARS-CoV-2 Spike Glycoprotein

Infectious Disorders - Drug Targets ◽

10.2174/1871526520666200804161650 ◽

2020 ◽

Vol 20 ◽

Author(s):

Bipin Singh

Keyword(s):

Receptor Binding ◽

Point Mutations ◽

Binding Domain ◽

Receptor Binding Domain ◽

Spike Glycoprotein ◽

Angiotensin Converting Enzyme 2 ◽

Recent Outbreak ◽

Novel Coronavirus ◽

Genomic Similarity

: The recent outbreak of novel coronavirus (SARS-CoV-2 or 2019-nCoV) and its worldwide spread is posing one of the major threats to human health and the world economy. It has been suggested that SARS-CoV-2 is similar to SARSCoV based on the comparison of the genome sequence. Despite the genomic similarity between SARS-CoV-2 and SARSCoV, the spike glycoprotein and receptor binding domain in SARS-CoV-2 shows the considerable difference compared to SARS-CoV, due to the presence of several point mutations. The analysis of receptor binding domain (RBD) from recently published 3D structures of spike glycoprotein of SARS-CoV-2 (Yan, R., et al. (2020); Wrapp, D., et al. (2020); Walls, A. C., et al. (2020)) highlights the contribution of a few key point mutations in RBD of spike glycoprotein and molecular basis of its efficient binding with human angiotensin-converting enzyme 2 (ACE2).

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