In silico targeting of SARS-CoV-2 spike receptor-binding domain from different variants with chaga mushroom terpenoids.

Terpenoids from the chaga mushroom have been identified as potential antiviral agents against SARS-CoV-2. This is because it can firmly bind to the viral spike receptor binding domain (RBD) and the auxiliary host cell receptor glucose-regulated protein 78 (GRP78). The current work examines the association of the chaga mushroom terpenoids with the RBD of various SARS-CoV-2 variants, including alpha, beta, gamma, delta, and omicron. This association was compared to the SARS-CoV-2 wild-type (WT) RBD using molecular docking analysis and molecular dynamics modeling. The outcomes demonstrated that the mutant RBDs, which had marginally greater average binding affinities (better binding) than the WT, were successfully inhibited by the chaga mushroom terpenoids. The results suggest that the chaga mushroom can be effective against various SARS-CoV-2 variants by targeting both the host-cell surface receptor GRP78 and the viral spike RBD.Communicated by Ramaswamy H. Sarma.

Potential antiviral peptides targeting the SARS-CoV-2 spike protein.

BACKGROUND: The coronavirus disease caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection became an international pandemic and created a public health crisis. The binding of the viral Spike glycoprotein to the human cell receptor angiotensin-converting enzyme 2 (ACE2) initiates viral infection. The development of efficient treatments to combat coronavirus disease is considered essential. METHODS: An in silico approach was employed to design amino acid peptide inhibitor against the receptor-binding domain (RBD) of the SARS-CoV-2 spike protein. The designed inhibitor (SARS-CoV-2 PEP 49) consists of amino acids with the α1 helix and the ß4 - ß5 sheets of ACE2. The PEP-FOLD3 web tool was used to create the 3D structures of the peptide amino acids. Analyzing the interaction between ACE2 and the RBD of the Spike protein for three protein data bank entries (6M0J, 7C8D, and 7A95) indicated that the interacting amino acids were contained inside two regions of ACE2: the α1 helical protease domain (PD) and the ß4 - ß5 sheets. RESULTS: Molecular docking analysis of the designed inhibitor demonstrated that SARS-CoV-2 PEP 49 attaches directly to the ACE2 binding site of the Spike protein with a binding affinity greater than the ACE2, implying that the SARS-CoV-2 PEP 49 model may be useful as a potential RBD binding blocker.

Seeking antiviral drugs to inhibit SARS-CoV-2 RNA dependent RNA polymerase: A molecular docking analysis.

COVID-19 outbreak associated with the severe acute respiratory syndrome coronavirus (SARS-CoV-2) raised health concerns across the globe and has been considered highly transmissible between people. In attempts for finding therapeutic treatment for the new disease, this work has focused on examining the polymerase inhibitors against the SARS-CoV-2 nsp12 and co-factors nsp8 and nsp7. Several polymerase inhibitors were examined against PDB ID: 6M71 using computational analysis evaluating the ligand's binding affinity to replicating groove to the active site. The findings of this analysis showed Cytarabine of -5.65 Kcal/mol with the highest binding probability (70%) to replicating groove of 6M71. The complex stability was then examined over 19 ns molecular dynamics simulation suggesting that Cytarabine might be possible potent inhibitor for the SARS-CoV-2 RNA Dependent RNA Polymerase.

SARS-CoV-2 variant surge and vaccine breakthrough infection: A computational analysis.

Coronavirus Delta variant was first detected in India in October of 2020, and it led to a massive second wave of COVID-19 cases in the country. Since then, the highly infectious Delta strain has been spreading globally. The Delta variant and its sub-lineages showed an increased infection rate with a reduced effect of the potential antibody neutralization. The current work is a modeled computational analysis of the mutated receptor-binding domain (RBD) of the SARS-CoV-2 B.1.617 lineage binding with ACE2 and GRP78 to understand the increased strain transmissibility. The cell-surface Glucose Regulated Protein 78 (GRP78) attached to the mutated ACE2-SARS-CoV-2 Spike RBD complex is modeled. The results showed that GRP78 ß-substrate-binding domain weakly binds to the wild-type RBD combined with angiotensin-converting enzyme 2 (ACE2) within the SARS-CoV-2 Spike RBD-ACE2 complex. Both GRP78 and ACE2 bind approximately in the same region on the wild-type SARS-CoV-2 Spike RBD surface. On the other hand, GRP78 strongly binds to the mutated SARS-CoV-2 Spike RBD in the RBD-ACE2 complex through the α-substrate-binding domain instead of ß-substrate-binding domain in a different region from that of ACE2. The current findings suggest that blocking the main ACE2 pathway may not prevent the interactions between GRP78 and the mutated SARS-CoV-2 Spike RBD, which might introduce an additional avenue into the virus invasion for the host cell if the ACE2 pathway is blocked by the neutralized antibodies. Hence, the peptide satpdb10668 has been proposed as a potential inhibitor of SARS-CoV-2 attachment and virus invasion into the host cell.

A Review of Human Coronaviruses' Receptors: The Host-Cell Targets for the Crown Bearing Viruses.

A novel human coronavirus prompted considerable worry at the end of the year 2019. Now, it represents a significant global health and economic burden. The newly emerged coronavirus disease caused by the severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) is the primary reason for the COVID-19 global pandemic. According to recent global figures, COVID-19 has caused approximately 243.3 million illnesses and 4.9 million deaths. Several human cell receptors are involved in the virus identification of the host cells and entering them. Hence, understanding how the virus binds to host-cell receptors is crucial for developing antiviral treatments and vaccines. The current work aimed to determine the multiple host-cell receptors that bind with SARS-CoV-2 and other human coronaviruses for the purpose of cell entry. Extensive research is needed using neutralizing antibodies, natural chemicals, and therapeutic peptides to target those host-cell receptors in extremely susceptible individuals. More research is needed to map SARS-CoV-2 cell entry pathways in order to identify potential viral inhibitors.

In silico molecular docking analysis for repurposing approved antiviral drugs against SARS-CoV-2 main protease.

Developing a safe and effective antiviral treatment takes a decade, however, when it comes to the coronavirus disease (COVID-19), time is a sensitive matter to slow the spread of the pandemic. Screening approved antiviral drugs against COVID-19 would speed the process of finding therapeutic treatment. The current study examines commercially approved drugs to repurpose them against COVID-19 virus main protease using structure-based in-silico screening. The main protease of the coronavirus is essential in the viral replication and is involved in polyprotein cleavage and immune regulation, making it an effective target when developing the treatment. A Number of approved antiviral drugs were tested against COVID-19 virus using molecular docking analysis by calculating the free natural affinity of the binding ligand to the active site pocket and the catalytic residues without forcing the docking of the ligand to active site. COVID-19 virus protease solved structure (PDB ID: 6LU7) is targeted by repurposed drugs. The molecular docking analysis results have shown that the binding of Remdesivir and Mycophenolic acid acyl glucuronide with the protein drug target has optimal binding features supporting that Remdesivir and Mycophenolic acid acyl glucuronide can be used as potential anti-viral treatment against COVID-19 disease.