In silico analysis of the interactions of certain flavonoids with the receptor-binding domain of 2019 novel coronavirus and cellular proteases and their pharmacokinetic properties

: 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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Effect of An 84-bp Deletion of the Receptor-Binding Domain on the ACE2 Binding Affinity of the SARS-CoV-2 Spike Protein: An In Silico Analysis

Genes ◽

10.3390/genes12020194 ◽

2021 ◽

Vol 12 (2) ◽

pp. 194

Author(s):

Gábor Kemenesi ◽

Gábor Endre Tóth ◽

Dávid Bajusz ◽

György M. Keserű ◽

Gabriella Terhes ◽

...

Keyword(s):

Receptor Binding ◽

Early Recognition ◽

In Silico Analysis ◽

Genetic Alterations ◽

Binding Domain ◽

Spike Protein ◽

Evolutionary Strategy ◽

Receptor Binding Domain ◽

Base Pair Deletion ◽

Therapeutic Research

SARS-CoV-2 is a recently emerged, novel human coronavirus responsible for the currently ongoing COVID-19 pandemic. Recombination is a well-known evolutionary strategy of coronaviruses, which may frequently result in significant genetic alterations, such as deletions throughout the genome. In this study we identified a co-infection with two genetically different SARS-CoV-2 viruses within a single patient sample via amplicon-based next generation sequencing in Hungary. The recessive strain contained an 84 base pair deletion in the receptor binding domain of the spike protein gene and was found to be gradually displaced by a dominant non-deleterious variant over-time. We have identified the region of the receptor-binding domain (RBD) that is affected by the mutation, created homology models of the RBDΔ84 mutant, and based on the available experimental data and calculations, we propose that the mutation has a deteriorating effect on the binding of RBD to the angiotensin-converting enzyme 2 (ACE2) receptor, which results in the negative selection of this variant. Extending the sequencing capacity toward the discovery of emerging recombinant or deleterious strains may facilitate the early recognition of novel strains with altered phenotypic attributes and understanding of key elements of spike protein evolution. Such studies may greatly contribute to future therapeutic research and general understanding of genomic processes of the virus.

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An in Silico Scientific Basis for LL-37 as a Therapeutic and Vitamin D as Preventive for Covid-19.

10.26434/chemrxiv.12928202.v1 ◽

2020 ◽

Author(s):

Kiran Bharat Lokhande ◽

Tanushree Banerjee ◽

K. Venkateswara Swamy ◽

Manisha Deshpande

Keyword(s):

Vitamin D ◽

Receptor Binding ◽

In Silico ◽

Large Body ◽

Inverse Correlation ◽

Medical Practitioner ◽

Binding Domain ◽

The Body ◽

Receptor Binding Domain ◽

Vitamin D Levels

Even as clinical trials are underway for vaccines and therapeutics for Covid-19, establishment of modalities with a strong and complete foundation is still awaited and until then, the uncertainty remains associated. Thus, there is a requirement to research as many new and different types of approaches as possible to tackle the pandemic. In this report, in silico scientific findings are presented, which are indicative of the putative potential for the use of the LL-37 human anti-microbial peptide as a therapeutic or possibly even as a prophylactic against SARS-CoV-2. This indication is mainly based on the high structural similarity of LL-37 to the N-terminal helix of the receptor-binding domain of SARS-CoV-2, and the positive prediction of binding of LL-37 to the receptor-binding domain of SARS-CoV-2. Also, as Vitamin D is known to upregulate the expression of LL-37, the vitamin is a candidate preventive molecule. This report also provides the possible basis for why there is an inverse correlation between Vitamin D levels in the body and the severity of or susceptibility to Covid-19, as described in a large body of published literature. The path for development of LL-37 as a therapeutic could be of lesser duration, as LL-37 is native to the human body. With the scientific link put forth in this work, Vitamin D could be used at an effective, medically prescribed dose as a preventive measure. As Vitamin D is insoluble in water, it should be taken only in consultation with a medical practitioner to prevent adverse effects of its accumulation in the body. The information in this report would be valuable in bolstering the worldwide efforts to control the pandemic as early as possible.

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Cross-reactive neutralization of SARS-CoV-2 by serum antibodies from recovered SARS patients and immunized animals

Science Advances ◽

10.1126/sciadv.abc9999 ◽

2020 ◽

Vol 6 (45) ◽

pp. eabc9999 ◽

Cited By ~ 4

Author(s):

Yuanmei Zhu ◽

Danwei Yu ◽

Yang Han ◽

Hongxia Yan ◽

Huihui Chong ◽

...

Keyword(s):

Severe Acute Respiratory Syndrome ◽

Receptor Binding ◽

Binding Domain ◽

Full Length ◽

Receptor Binding Domain ◽

Serum Antibodies ◽

Serum Samples ◽

S Protein ◽

Novel Coronavirus

The current coronavirus disease 2019 (COVID-19) pandemic is caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), a novel coronavirus genetically close to SARS-CoV. To investigate the effects of previous SARS-CoV infection on the ability to recognize and neutralize SARS-CoV-2, we analyzed 20 convalescent serum samples collected from individuals infected with SARS-CoV during the 2003 SARS outbreak. All patient sera reacted strongly with the S1 subunit and receptor binding domain (RBD) of SARS-CoV; cross-reacted with the S ectodomain, S1, RBD, and S2 proteins of SARS-CoV-2; and neutralized both SARS-CoV and SARS-CoV-2 S protein–driven infections. Analysis of antisera from mice and rabbits immunized with a full-length S and RBD immunogens of SARS-CoV verified cross-reactive neutralization against SARS-CoV-2. A SARS-CoV–derived RBD from palm civets elicited more potent cross-neutralizing responses in immunized animals than the RBD from a human SARS-CoV strain, informing strategies for development of universal vaccines against emerging coronaviruses.

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In silico analysis and identification of promising hits against 2019 novel coronavirus 3C-like main protease enzyme

Journal of Biomolecular Structure and Dynamics ◽

10.1080/07391102.2020.1787228 ◽

2020 ◽

pp. 1-14 ◽

Cited By ~ 1

Author(s):

Shilpa Chatterjee ◽

Arindam Maity ◽

Suchana Chowdhury ◽

Md Ataul Islam ◽

Ravi K. Muttinini ◽

...

Keyword(s):

In Silico ◽

In Silico Analysis ◽

Protease Enzyme ◽

Main Protease ◽

Novel Coronavirus ◽

Silico Analysis

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Computational Approach Revealed Potential Affinity of Antiasthmatics Against Receptor Binding Domain of 2019n-Cov Spike Glycoprotein

10.26434/chemrxiv.12115638.v1 ◽

2020 ◽

Author(s):

LAMIAE ELKHATTABI ◽

Hicham Charoute ◽

Rachid Saile ◽

Abdelhamid Barakat

Keyword(s):

Molecular Docking ◽

Receptor Binding ◽

In Silico ◽

Cyclic Peptide ◽

Direct Interaction ◽

Binding Domain ◽

Binding Energies ◽

Receptor Binding Domain ◽

Spike Glycoprotein ◽

Pubchem Database

The novel COVID-19 pandemic is now a health threat, with a deep-felt impact worldwide. The new coronavirus 2019 (2019 n-Cov) binds to host human receptors through Receptor Binding Domain RBD of Spike glycoprotein (S), making it a prominent drug target. The present study aims to identify new potential hits that can inhibit the S protein using in silico approaches. Several natural and synthetics compounds (antiasthmatics, Antiviral, Antimalarial, Antibacterial, Anti-Inflammatory, cyclic peptide, and cyclic bis) were screened by molecular docking using AutoDock Vina. Additionally, we tested calcitriol and three known drugs (Azithromycin, HydroxyChloroquine, and Chloroquine ) against the spike protein to found if they have any direct interaction. Our finding consists of 4 potential synthetic compounds from PubChem database, known for their antiasthmatic effects, that show highly binding energies each (-8.6 kcal/mol, 7.7kcal/mol, -7.2 kcal/mol and -7.0 kcal/mol). Another 5 natural compounds from the South African natural sources database (SANCDB) that bind to RBD of Spike with significant energy each: (Marchantin C with -7.3 kcal/mol, Riccardin C with -7.0 kcal/mol, Digitoxigenin-glucoside with -6.9 kcal/mol, D-Friedoolean-14-en-oic acid with -6.8 kcal/mol and, Spongotine A with -6.7 kcal/mol). The FaF-Drugs server was used to evaluate the drug-like properties of the identified compounds. Additionally, Calcitriol, Azithromycin, and HydroxyChloroquine have an appreciable binding affinity to 2019-nCoV S, suggesting a possible mechanism of action. Using in silico approaches like molecular docking and pharmacokinetic properties, we showed new potential inhibitors. Our findings need further analysis, and chemical design for more effective derivatives of these compounds speculated to disrupt the viral recognition of host receptors.

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A Structural Landscape of Neutralizing Antibodies Against SARS-CoV-2 Receptor Binding Domain

Frontiers in Immunology ◽

10.3389/fimmu.2021.647934 ◽

2021 ◽

Vol 12 ◽

Author(s):

Ling Niu ◽

Kathryn N. Wittrock ◽

Gage C. Clabaugh ◽

Vikram Srivastava ◽

Michael W. Cho

Keyword(s):

Receptor Binding ◽

Neutralizing Antibodies ◽

Critical Role ◽

Binding Domain ◽

The Novel ◽

Receptor Binding Domain ◽

Correlates Of Protection ◽

Immune Correlates ◽

Virus Life Cycle ◽

Novel Coronavirus

SARS-CoV-2, the novel coronavirus responsible for the ongoing COVID-19 pandemic, has been spreading rampantly. The global scientific community has responded rapidly to understand immune correlates of protection to develop vaccines and immunotherapeutics against the virus. The major goal of this mini review is to summarize current understanding of the structural landscape of neutralizing antibodies (nAbs) that target the receptor binding domain (RBD) of viral spike (S) glycoprotein. The RBD plays a critical role in the very first step of the virus life cycle. Better understanding of where and how nAbs bind the RBD should enable identification of sites of vulnerability and facilitate better vaccine design and formulation of immunotherapeutics. Towards this goal, we compiled 38 RBD-binding nAbs with known structures. Review of these nAb structures showed that (1) nAbs can be divided into five general clusters, (2) there are distinct non-neutralizing faces on the RBD, and (3) maximum of potentially four nAbs could bind the RBD simultaneously. Since most of these nAbs were isolated from virus-infected patients, additional analyses of vaccine-induced nAbs could facilitate development of improved vaccines.

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