In silico design of peptides with binding to the receptor binding domain (RBD) of the SARS-CoV-2 and their utility in bio-sensor development for SARS-CoV-2 detection

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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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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In-silico design of a multi-epitope recombinant vaccine against SARS-CoV-2 targeting the receptor binding domain

10.31219/osf.io/cg6e3 ◽

2020 ◽

Author(s):

Harshawardhan Pande

Keyword(s):

T Cell ◽

B Cell ◽

Receptor Binding ◽

In Silico ◽

Neutralizing Antibodies ◽

De Novo ◽

Recombinant Vaccine ◽

Binding Domain ◽

Surface Glycoprotein ◽

Receptor Binding Domain

The COVID-19 pandemic caused by the SARS-CoV-2 virus is posing a major global challenge due to its rapid infectivity and lethality. Despite a global effort towards creating a vaccine, no viable vaccine currently exists. While multiple bioinformatic studies have attempted to predict epitopes, they have focused on the whole spike protein without considering antibody mediated enhancement or Th-2 immunopathology and have missed some important but less antigenic epitopes in the receptor binding domain. Therefore, this study used in silico methods to design and evaluate a potential multiepitope vaccine that specifically targets the receptor binding domain due to its critical function in viral entry. Immunoinformatic tools were used to specifically examine the receptor binding domain of the surface glycoprotein for suitable T cell and B cell epitopes. The selected 5 B cell and 8 T cell epitopes were then constructed into a subunit vaccine and appropriate adjuvants along with the universal immunogenic PADRE sequence were added to boost efficacy. The structure of the vaccine construct was predicted through a de novo approach and molecular docking simulations were performed which demonstrated high affinity binding to TLR 5 receptor and appropriate HLA proteins. Finally, the vaccine candidate was cloned into an expression vector for use as a recombinant vaccine. Similarities to some recent epitope mapping studies suggest a high potential for eliciting neutralizing antibodies and generating a favorable overall immune response.

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Design and Synthesis of De Novo Boomerang Shaped Molecules and their In Silico & SERS-based Interactions with SARS-CoV-2 Spike Protein and ACE2

New Journal of Chemistry ◽

10.1039/d1nj02955j ◽

2021 ◽

Author(s):

Amrutham Linet ◽

Manu M Joseph ◽

Haritha Mambatta ◽

Shamna k ◽

Sunil varughese ◽

...

Keyword(s):

Severe Acute Respiratory Syndrome ◽

Receptor Binding ◽

In Silico ◽

De Novo ◽

Binding Domain ◽

Spike Protein ◽

Epithelial Tissue ◽

Receptor Binding Domain ◽

Design And Synthesis ◽

Recent Outbreak

The recent outbreak of the COVID-19 pandemic is caused by severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2), which infects human epithelial tissue by interaction of the receptor-binding domain of its spike...

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Application of an integrated computational antibody engineering platform to design SARS-CoV-2 neutralizers

Antibody Therapeutics ◽

10.1093/abt/tbab011 ◽

2021 ◽

Author(s):

Saleh Riahi ◽

Jae Hyeon Lee ◽

Shuai Wei ◽

Robert Cost ◽

Alessandro Masiero ◽

...

Keyword(s):

Binding Affinity ◽

Receptor Binding ◽

In Silico ◽

Half Life ◽

Neutralizing Antibodies ◽

Binding Domain ◽

Antibody Engineering ◽

Receptor Binding Domain ◽

Effector Functions

Abstract As the COVID-19 pandemic continues to spread, hundreds of new initiatives including studies on existing medicines are running to fight the disease. To deliver a potentially immediate and lasting treatment to current and emerging SARS-CoV-2 variants, new collaborations and ways of sharing are required to create as many paths forward as possible. Here we leverage our expertise in computational antibody engineering to rationally design/engineer three previously reported SARS-CoV neutralizing antibodies and share our proposal towards anti-SARS-CoV-2 biologics therapeutics. SARS-CoV neutralizing antibodies, m396, 80R, and CR-3022 were chosen as templates due to their diversified epitopes and confirmed neutralization potency against SARS-CoV (but not SARS-CoV-2 except for CR3022). Structures of variable fragment (Fv) in complex with receptor binding domain (RBD) from SARS-CoV or SARS-CoV-2 were subjected to our established in silico antibody engineering platform to improve their binding affinity to SARS-CoV-2 and developability profiles. The selected top mutations were ensembled into a focused library for each antibody for further screening. In addition, we convert the selected binders with different epitopes into the trispecific format, aiming to increase potency and to prevent mutational escape. Lastly, to avoid antibody induced virus activation or enhancement, we suggest application of NNAS and DQ mutations to the Fc region to eliminate effector functions and extend half-life.

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Targeting the glycan of receptor binding domain with jacalin as a novel approach to develop a treatment against COVID-19

Royal Society Open Science ◽

10.1098/rsos.200844 ◽

2020 ◽

Vol 7 (9) ◽

pp. 200844

Author(s):

Senthilnathan Rajendaran ◽

Arunchalam Jothi ◽

Veerappan Anbazhagan

Keyword(s):

Angiotensin Converting Enzyme ◽

Receptor Binding ◽

Conformational Changes ◽

In Silico ◽

Binding Domain ◽

Receptor Binding Domain ◽

Converting Enzyme ◽

Angiotensin Converting Enzyme 2 ◽

Novel Approach

In silico analysis revealed that a lectin, jacalin from jackfruit seeds, recognizes a glycosylated region of the receptor-binding domain (RBD) of SARS-CoV2. Jacalin binding induces conformational changes in RBD and significantly affects its interaction with human angiotensin-converting enzyme 2. The result may open up exploration of lectin-based strategies against COVID-19.

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Targeting SARS-CoV-2 Receptor Binding Domain with Stapled Peptides: An In Silico Study

The Journal of Physical Chemistry B ◽

10.1021/acs.jpcb.1c02398 ◽

2021 ◽

Author(s):

Luana Janaína de Campos ◽

Nicholas Y. Palermo ◽

Martin Conda-Sheridan

Keyword(s):

Receptor Binding ◽

In Silico ◽

Binding Domain ◽

Receptor Binding Domain ◽

Stapled Peptides ◽

In Silico Study

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In Silico Identification of Potential Therapeutic Agents for COVID-19 Based on Molecular Docking Study of Main Protease and Receptor Binding Domain of Spike Protein.

10.21203/rs.3.rs-285026/v1 ◽

2021 ◽

Author(s):

Vajiheh Eskandari

Keyword(s):

Folic Acid ◽

Receptor Binding ◽

In Silico ◽

Docking Study ◽

Binding Domain ◽

Dynamics Simulation ◽

Receptor Binding Domain ◽

Active Site Residues ◽

Molecular Docking Study ◽

S Protein

Abstract Severe acute respiratory syndrome coronavirus (SARS-CoV-2) enter the cell by interacting with human angiotensin-converting enzyme 2 (ACE2) receptor through the receptor-binding domain (RBD) of S-protein. In the cell the viral 3-chymotrypsin-like cysteine protease (3CLp) enzyme is essential for its life cycle and controls coronavirus replication. Therefore the S-RBD and 3CLp are hot targets for drugs discovery against SARS-CoV-2. This study was to identify repurposing drugs using in-silico screening, docking and molecular dynamics simulation. The study identified Dibenzoyl Thiamine, Folic Acid and Vitamin B12 against the RBD of S-protein and Dibenzoyl Thiamine, Folic Acid, Fursultiamine and Riboflavin to 3CLp. The strong and stable binding of these safe and cheap vitamins at the important residues (R403, K417, Y449, Y453, N501 and Y505) in S-protein –ACE2 interface and 3CLp active site residues (His 41 and Cys 145), indicating that they could be valuable repurpose drugs for inhibiting SARS-CoV-2 entry into the host and replication.

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Application of an integrated computational antibody engineering platform to design SARS-CoV-2 neutralizers

10.1101/2021.03.23.436613 ◽

2021 ◽

Author(s):

Saleh Riahi ◽

Jae Hyeon Lee ◽

Shuai Wei ◽

Robert Cost ◽

Alessandro Masiero ◽

...

Keyword(s):

Binding Affinity ◽

Receptor Binding ◽

In Silico ◽

Half Life ◽

Neutralizing Antibodies ◽

Binding Domain ◽

Antibody Engineering ◽

Receptor Binding Domain ◽

Effector Functions

As the COVID-19 pandemic continues to spread, hundreds of new initiatives including studies on existing medicines are running to fight the disease. To deliver a potentially immediate and lasting treatment to current and emerging SARS-CoV-2 variants, new collaborations and ways of sharing are required to create as many paths forward as possible. Here we leverage our expertise in computational antibody engineering to rationally design/optimize three previously reported SARS-CoV neutralizing antibodies and share our proposal towards anti-SARS-CoV-2 biologics therapeutics. SARS-CoV neutralizing antibodies, m396, 80R, and CR-3022 were chosen as templates due to their diversified epitopes and confirmed neutralization potency against SARS. Structures of variable fragment (Fv) in complex with receptor binding domain (RBD) from SARS-CoV or SARS-CoV2 were subjected to our established in silico antibody engineering platform to improve their binding affinity to SARS-CoV2 and developability profiles. The selected top mutations were ensembled into a focused library for each antibody for further screening. In addition, we convert the selected binders with different epitopes into the trispecific format, aiming to increase potency and to prevent mutational escape. Lastly, to avoid antibody induced virus activation or enhancement, we applied NNAS and DQ mutations to the Fc region to eliminate effector functions and extend half-life.

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Mutational landscape and in silico structure models of SARS-CoV-2 spike receptor binding domain reveal key molecular determinants for virus-host interaction

BMC Molecular and Cell Biology ◽

10.1186/s12860-021-00403-4 ◽

2022 ◽

Vol 23 (1) ◽

Author(s):

Shijulal Nelson-Sathi ◽

P. K. Umasankar ◽

E. Sreekumar ◽

R. Radhakrishnan Nair ◽

Iype Joseph ◽

...

Keyword(s):

Amino Acid ◽

Receptor Binding ◽

Viral Entry ◽

In Silico ◽

Rna Virus ◽

Binding Domain ◽

Virus Infectivity ◽

Receptor Binding Domain ◽

Synonymous Mutations ◽

Binding Interface

Abstract Background SARS-CoV-2, the causative agent of COVID-19 pandemic is a RNA virus prone to mutations. Formation of a stable binding interface between the Receptor Binding Domain (RBD) of SARS-CoV-2 Spike (S) protein and Angiotensin-Converting Enzyme 2 (ACE2) of host is pivotal for viral entry. RBD has been shown to mutate frequently during pandemic. Although, a few mutations in RBD exhibit enhanced transmission rates leading to rise of new variants of concern, most RBD mutations show sustained ACE2 binding and virus infectivity. Yet, how all these mutations make the binding interface constantly favourable for virus remain enigmatic. This study aims to delineate molecular rearrangements in the binding interface of SARS-CoV-2 RBD mutants. Results Here, we have generated a mutational and structural landscape of SARS-CoV-2 RBD in first six months of the pandemic. We analyzed 31,403 SARS-CoV-2 genomes randomly across the globe, and identified 444 non-synonymous mutations in RBD that cause 49 distinct amino acid substitutions in contact and non-contact amino acid residues. Molecular phylogenetic analysis suggested independent emergence of RBD mutants. Structural mapping of these mutations on the SARS-CoV-2 Wuhan reference strain RBD and structural comparison with RBDs from bat-CoV, SARS-CoV, and pangolin-CoV, all bound to human or mouse ACE2, revealed several changes in the interfacial interactions in all three binding clusters. Interestingly, interactions mediated via N487 residue in cluster-I and Y449, G496, T500, G502 residues in cluster-III remained largely unchanged in all RBD mutants. Further analysis showed that these interactions are evolutionarily conserved in sarbecoviruses which use ACE2 for entry. Importantly, despite extensive changes in the interface, RBD-ACE2 stability and binding affinities were maintained in all the analyzed mutants. Taken together, these findings reveal how SARS-CoV-2 uses its RBD residues to constantly remodel the binding interface. Conclusion Our study broadly signifies understanding virus-host binding interfaces and their alterations during pandemic. Our findings propose a possible interface remodelling mechanism used by SARS-CoV-2 to escape deleterious mutations. Future investigations will focus on functional validation of in-silico findings and on investigating interface remodelling mechanisms across sarbecoviruses. Thus, in long run, this study may provide novel clues to therapeutically target RBD-ACE2 interface for pan-sarbecovirus infections.

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