Exploration of potential inhibitors for SARS-CoV-2 Mpro considering its mutants via structure-based drug design, molecular docking, MD simulations, MM/PBSA, and DFT calculations.

The main protease (Mpro) of SARS-COV-2 plays a vital role in the viral life cycle and pathogenicity. Due to its specific attributes, this 3-chymotrypsin like protease can be a reliable target for the drug design to combat COVID-19. Since the advent of COVID-19, Mpro has undergone many mutations. Here, the impact of 10 mutations based on their frequency and five more based on their proximity to the active site was investigated. For comparison purposes, the docking process was also performed against the Mpros of SARS-COV and MERS-COV. Four inhibitors with the highest docking score (11b, α-ketoamide 13b, Nelfinavir, and PF-07321332) were selected for the structure-based ligand design via fragment replacement, and around 2000 new compounds were thus obtained. After the screening of these new compounds, the pharmacokinetic properties of the best ones were predicted. In the last step, comparative molecular dynamics (MD) simulations, molecular mechanics Poisson-Boltzmann surface area calculations (MM/PBSA), and density functional theory calculations were performed. Among the 2000 newly designed compounds, three of them (NE1, NE2, and NE3), which were obtained by modifications of Nelfinavir, showed the highest affinity against all the Mpro targets. Together, NE1 compound is the best candidate for follow-up Mpro inhibition and drug development studies.

An overview of the vaccine platforms to combat COVID-19 with a focus on the subunit vaccines.

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is an emerging virus that has caused the recent coronavirus disease (COVID-19) global pandemic. The current approved COVID-19 vaccines have shown considerable efficiency against hospitalization and death. However, the continuation of the pandemic for more than two years and the likelihood of new strain emergence despite the global rollout of vaccination highlight the immediate need for the development and improvement of vaccines. mRNA, viral vector, and inactivated virus vaccine platforms were the first members of the worldwide approved vaccine list. Subunit vaccines. which are vaccines based on synthetic peptides or recombinant proteins, have been used in lower numbers and limited countries. The unavoidable advantages of this platform, including safety and precise immune targeting, make it a promising vaccine with wider global use in the near future. This review article summarizes the current knowledge on different vaccine platforms, focusing on the subunit vaccines and their clinical trial advancements against COVID-19.

In silico design of a multi-epitope vaccine against the spike and the nucleocapsid proteins of the Omicron variant of SARS-CoV-2.

Computational studies can comprise an effective approach to treating and preventing viral infections. Since 2019, the world has been dealing with the outbreak of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). The most important achievement in this short period of time in the effort to reduce morbidity and mortality was the production of vaccines and effective antiviral drugs. Although the virus has been significantly suppressed, it continues to evolve, spread, and evade the host's immune system. Recently, researchers have turned to immunoinformatics tools to reduce side effects and save the time and cost of traditional vaccine production methods. In the present study, an attempt has been made to design a multi-epitope vaccine with humoral and cellular immune response stimulation against the Omicron variant of SARS-CoV-2 by investigating new mutations in spike (S) and nucleocapsid (N) proteins. The population coverage of the vaccine was evaluated as appropriate compared to other studies. The results of molecular dynamics simulation and molecular mechanics/generalized Born surface area (MM/GBSA) calculations predict the stability and proper interaction of the vaccine with Toll-like receptor 4 (TLR-4) as an innate immune receptor. The results of the immune simulation show a significant increase in the coordinated response of IgM and IgG after the third injection of the vaccine. Also, in the continuation of the research, spike proteins from BA.4 and BA.5 lineages were screened by immunoinformatics filters and effective epitopes were suggested for vaccine design. Despite the high precision of computational studies, in-vivo and in-vitro research is needed for final confirmation.Communicated by Ramaswamy H. Sarma.

Insights into the structural peculiarities of the N-terminal and receptor binding domains of the spike protein from the SARS-CoV-2 Omicron variant.

Since the new variant of SARS-CoV-2, Omicron (BA.1) has raised serious concerns, it is important to investigate the effects of mutations in the NTD and RBD domains of the spike protein for the development of COVID-19 vaccines. In this study, computational analysis of the Wuhan and Omicron NTDs and RBDs in their unbound and bound states to mAb 4A8 and ACE2 were performed. In addition, the interaction of NTD with antibody and RBD with ACE2 were evaluated in the presence of long glycans. The results show that long glycans at the surface of NTDs can reduce the accessibility of protein epitopes, thereby reducing binding efficiency and neutralizing potency of specific antibodies. Also, our findings indicate that the existence of the long glycans result in increased stability and enhanced affinity of the RBD to ACE2 in the Wuhan and Omicron variant. Key residues that play an important role in increasing the structural stability of the protein were identified using RIN analysis and in the state of interaction with mAb 4A8 and ACE2 through per-residue decomposition analysis. Further, the results of the free energy binding calculation using MM/GBSA method show that the Omicron variant has a higher infectivity than the Wuhan. This study provides a better understanding of the structural changes in the spike protein and can be useful for the development of novel therapeutics.

Molecular dynamics and intrinsic disorder analysis of the SARS-CoV-2 Nsp1 structural changes caused by substitution and deletion mutations

SARS-CoV-2 non-structural protein 1 (Nsp1) is a virulence factor that inhibits the translation of host mRNAs and interacts with viral RNA. To date, hundreds of mutations (base substitutions, deletions, and insertions) have been reported in SARS-CoV-2 Nsp1. Despite the relevance of Nsp1, a few studies have been conducted to understand the effect of those mutations on Nsp1 structure and function. In this study, the effects of the most frequent mutations were investigated using molecular dynamics simulations. We found that several mutations profoundly affect the local intrinsic disorder predisposition, with most deletions increasing disorder propensity and replacement mutations inducing variable effects. We found that deletions Δ80–90 and Δ156–158 destabilise the protein structure. For example, the Δ156–158 cause a higher root-mean-square deviation (RMSD) and Rg values than those of the wild-type of SARS-CoV-2 Nsp1. We also found that the SARS-CoV-2 Nsp1 is slightly more disordered than its counterpart from SARS-CoV. A better understanding of the complexity and dynamic nature of interactions between intrinsically disordered segments of Nsp1 and ribosome subunits might help develop novel therapeutic countermeasures against the SARS-CoV-2 variants. [ FROM AUTHOR] Copyright of Molecular Simulation is the property of Taylor & Francis Ltd and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use. This may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full . (Copyright applies to all s.)

Tracking the pipeline: immunoinformatics and the COVID-19 vaccine design.

With the onset of the COVID-19 pandemic, the amount of data on genomic and proteomic sequences of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) stored in various databases has exponentially grown. A large volume of these data has led to the production of equally immense sets of immunological data, which require rigorous computational approaches to sort through and make sense of. Immunoinformatics has emerged in the recent decades as a field capable of offering this approach by bridging experimental and theoretical immunology with state-of-the-art computational tools. Here, we discuss how immunoinformatics can assist in the development of high-performance vaccines and drug discovery needed to curb the spread of SARS-CoV-2. Immunoinformatics can provide a set of computational tools to extract meaningful connections from the large sets of COVID-19 patient data, which can be implemented in the design of effective vaccines. With this in mind, we represent a pipeline to identify the role of immunoinformatics in COVID-19 treatment and vaccine development. In this process, a number of free databases of protein sequences, structures and mutations are introduced, along with docking web servers for assessing the interaction between antibodies and the SARS-CoV-2 spike protein segments as most commonly considered antigens in vaccine design.

Comparative molecular dynamics study of the receptor-binding domains in SARS-CoV-2 and SARS-CoV and the effects of mutations on the binding affinity.

Here, we report on a computational comparison of the receptor-binding domains (RBDs) on the spike proteins of severe respiratory syndrome coronavirus-2 (SARS-CoV-2) and SARS-CoV in free forms and as complexes with angiotensin-converting enzyme 2 (ACE2) as their receptor in humans. The impact of 42 mutations discovered so far on the structure and thermodynamics of SARS-CoV-2 RBD was also assessed. The binding affinity of SARS-CoV-2 RBD for ACE2 is higher than that of SARS-CoV RBD. The binding of COVA2-04 antibody to SARS-CoV-2 RBD is more energetically favorable than the binding of COVA2-39, but also less favorable than the formation of SARS-CoV-2 RBD-ACE2 complex. The net charge, the dipole moment and hydrophilicity of SARS-CoV-2 RBD are higher than those of SARS-CoV RBD, producing lower solvation and surface free energies and thus lower stability. The structure of SARS-CoV-2 RBD is also more flexible and more open, with a larger solvent-accessible surface area than that of SARS-CoV RBD. Single-point mutations have a dramatic effect on distribution of charges, most prominently at the site of substitution and its immediate vicinity. These charge alterations alter the free energy landscape, while X→F mutations exhibit a stabilizing effect on the RBD structure through π stacking. F456 and W436 emerge as two key residues governing the stability and affinity of the spike protein for its ACE2 receptor. These analyses of the structural differences and the impact of mutations on different viral strains and members of the coronavirus genera are an essential aid in the development of effective therapeutic strategies. Communicated by Ramaswamy H. Sarma.