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    Modeling Substrate Coordination to Zn-Bound Angiotensin Converting Enzyme HGNC 2

    Authors: Peter R. Fatouros; Urmi Roy; Shantanu Sur

    doi:10.1101/2021.03.27.437352 Date: 2021-03-29 Source: bioRxiv

    The spike protein PROTEIN in the envelope of severe acute respiratory syndrome coronavirus 2 MESHD (SARS-CoV-2) interacts with the receptor Angiotensin Converting Enzyme 2 (ACE2) on the host cell to facilitate the viral uptake. Angiotensin II HGNC (Ang II) peptide, which has a naturally high affinity for ACE2, may be useful in inhibiting this interaction. In this study, we computationally designed several Ang II mutants to find a strong binding sequence to ACE2 receptor and examined the role of ligand substitution in the docking of native as well as mutant Ang II to the ACE2 receptor. The peptide in the ACE2-peptide complex was coordinated to zinc in the ACE2 cleft. Exploratory molecular dynamics ( MD MESHD) simulations were used to measure the time-based stability of the native and mutant peptides and their receptor complexes. The MD-generated root-mean-square deviation (RMSD) values are mostly similar between the native and seven mutant peptides considered in this work, although the values for free peptides demonstrated higher variation, and often were higher in amplitude than peptides associated with the ACE2 complex. An observed lack of a strong secondary structure in the short peptides is attributed to the latter's greater flexibility and movement. The strongest binding energies within the ACE2-peptide complexes were observed in the native Ang II and only one of its mutant variants, suggesting ACE2 cleft is designed to provide optimal binding to the native sequence. An examination of the S1 binding site on ACE2 suggests that complex formation alone with these peptides may not be sufficient to allosterically inhibit the binding of SARS-CoV-2 spike PROTEIN proteins. However, it opens up the potential for utilizing AngII-ACE2 binding in the future design of molecular and supramolecular structures to prevent spike protein PROTEIN interaction with the receptor through creation of steric hindrance.

    Carnosine to Combat Novel Coronavirus (nCoV, COVID-19 MESHD): Molecular Docking and Modeling to Co-Crystallized Host Angiotensin-Converting Enzyme 2 HGNC ( ACE2 HGNC) and Viral Spike Protein PROTEIN

    Authors: Loai M. Saadah; Ghina’a I Abu Deiab; Qosay Al-Balas; Iman A. Basheti

    id:10.20944/preprints202010.0486.v1 Date: 2020-10-23 Source: Preprints.org

    Aims: Angiotensin-converting enzyme 2 HGNC ( ACE2 HGNC) plays an important role in the entry of coronaviruses into host cells. This paper described how carnosine, a naturally occurring supplement, can be an effective drug candidate for coronavirus disease MESHD ( COVID-19 MESHD) on the basis of molecular docking and modeling to host ACE2 HGNC co-crystallized with COVID-19 MESHD spike protein PROTEIN. Methods: First, the starting point was ACE2 HGNC inhibitors and their structure-activity relationship ( SAR HGNC). Next, chemical similarity (or diversity) and PubMed searches made it possible to repurpose and assess approved or experimental drugs for COVID-19 MESHD. In parallel, at all stages, authors performed bioactivity scoring to assess potential repurposed inhibitors at ACE2 HGNC. Finally, investigators performed molecular docking and modeling of the identified drug candidate to host ACE2 HGNC co-crystallized with COVID-19 MESHD spike protein PROTEIN. Results: Carnosine emerged as the best known drug candidate to match ACE2 HGNC inhibitor structure. Preliminary docking was more optimal to ACE2 HGNC than the known typical angiotensin-converting enzyme 1 ( ACE1 HGNC) inhibitor (enalapril) and quite comparable to known or presumed ACE2 HGNC inhibitors. Viral spike protein PROTEIN elements binding to ACE2 HGNC were retained in the best carnosine pose in SwissDock at 1.75 Angstroms. Out of the three main areas of attachment expected to the co-crystallized protein structure, carnosine bind with higher affinity to two compared to the known ACE2 HGNC active site. LibDock score was 92.40 for site 3, 90.88 for site 1, and inside the active site 85.49. Conclusion: Carnosine has promising inhibitory interactions with host ACE2 HGNC co-crystallized with COVID-19 MESHD spike protein PROTEIN and hence could offer potential mitigating effect against current COVID-19 pandemic MESHD.

    Supervised molecular dynamics for exploring the druggability of the SARS-CoV-2 spike PROTEIN protein

    Authors: Giuseppe Deganutti; Filippo Prischi; Christopher A. Reynolds

    doi:10.21203/rs.3.rs-64722/v1 Date: 2020-08-24 Source: ResearchSquare

    The recent outbreak of the respiratory syndrome MESHD-related coronavirus (SARS-CoV-2) is stimulating an unprecedented scientific campaign to alleviate the burden of the coronavirus disease MESHD ( COVID-19 MESHD). One line of research has focused on targeting SARS-CoV-2 proteins fundamental for its replication by repurposing drugs approved for other diseases. The first interaction between the virus and the host cell is mediated by the spike protein PROTEIN on the virus surface and the human angiotensin-converting enzyme HGNC ( ACE2 HGNC). Small molecules able to bind the receptor-binding domain (RBD) of the spike protein PROTEIN and disrupt the binding to ACE2 HGNC would offer an important tool for slowing, or even preventing, the infection. Here, we screened 2421 approved small molecules in silico and validated the docking outcomes through extensive molecular dynamics simulations. Out of six drugs characterized as putative RBD binders, the cephalosporin antibiotic cefsulodin was further assessed for its effect on the binding between the RBD and ACE2 HGNC, suggesting the importance of considering the dynamic formation of the heterodimer when judging any potential candidate.

    Repurposing of Approved Drugs with Potential to Interact with SARS-CoV-2 Receptor

    Authors: Abu Sajib

    id:202004.0369/v2 Date: 2020-08-02 Source: Preprints.org

    Respiratory transmission is the primary route of Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) infection MESHD. Angiotensin I converting enzyme 2 HGNC ( ACE2 HGNC) is the known receptor of SARS-CoV-2 surface spike glycoprotein PROTEIN for entry into human cells. A recent study reported absent to low expression of ACE2 HGNC in a variety of human lung epithelial cell samples. Three bioprojects (PRJEB4337, PRJNA270632 and PRJNA280600) invariably found abundant expression of ACE1 HGNC (a homolog of ACE2 HGNC and also known as ACE HGNC) in human lungs compared to very low expression of ACE2 HGNC. In fact, ACE1 HGNC has a wider and more abundant tissue distribution compared to ACE2 HGNC. Although it is not obvious from the primary sequence alignment of ACE1 HGNC and ACE2 HGNC, comparison of X-ray crystallographic structures show striking similarities in the regions of the peptidase domains (PD) of these proteins, which is known (for ACE2 HGNC) to interact with the receptor binding domain (RBD) of the SARS-CoV-2 spike PROTEIN protein. Critical amino acids in ACE2 HGNC that mediate interaction with the viral spike protein PROTEIN are present and organized in the same order in the PD of ACE1 HGNC. In silico analysis predicts comparable interaction of SARS-CoV-2 spike PROTEIN protein with ACE1 HGNC and ACE2 HGNC. In addition, this study predicts from a list of 1263 already approved drugs that may interact with ACE2 HGNC and/or ACE1 HGNC, potentially interfere with the entry of SARS-CoV-2 inside the host cells and alleviate the symptoms of Coronavirus disease MESHD ( COVID-19 MESHD).

    Repurposing of Approved Drugs with Potential to Interact with SARS-CoV-2 Receptor

    Authors: Abu Sajib

    id:10.20944/preprints202004.0369.v2 Date: 2020-08-02 Source: Preprints.org

    Respiratory transmission is the primary route of Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) infection MESHD. Angiotensin I converting enzyme 2 HGNC ( ACE2 HGNC) is the known receptor of SARS-CoV-2 surface spike glycoprotein PROTEIN for entry into human cells. A recent study reported absent to low expression of ACE2 HGNC in a variety of human lung epithelial cell samples. Three bioprojects (PRJEB4337, PRJNA270632 and PRJNA280600) invariably found abundant expression of ACE1 HGNC (a homolog of ACE2 HGNC and also known as ACE HGNC) in human lungs compared to very low expression of ACE2 HGNC. In fact, ACE1 HGNC has a wider and more abundant tissue distribution compared to ACE2 HGNC. Although it is not obvious from the primary sequence alignment of ACE1 HGNC and ACE2 HGNC, comparison of X-ray crystallographic structures show striking similarities in the regions of the peptidase domains (PD) of these proteins, which is known (for ACE2 HGNC) to interact with the receptor binding domain (RBD) of the SARS-CoV-2 spike PROTEIN protein. Critical amino acids in ACE2 HGNC that mediate interaction with the viral spike protein PROTEIN are present and organized in the same order in the PD of ACE1 HGNC. In silico analysis predicts comparable interaction of SARS-CoV-2 spike PROTEIN protein with ACE1 HGNC and ACE2 HGNC. In addition, this study predicts from a list of 1263 already approved drugs that may interact with ACE2 HGNC and/or ACE1 HGNC, potentially interfere with the entry of SARS-CoV-2 inside the host cells and alleviate the symptoms of Coronavirus disease MESHD ( COVID-19 MESHD).

    Type 1 diabetes onset triggered by COVID-19 MESHD

    Authors: Lucien Marchand; Matthieu Pecquet; Cédric Luyton

    doi:10.21203/rs.3.rs-38116/v1 Date: 2020-06-27 Source: ResearchSquare

    The epidemic of coronavirus disease-2019 ( COVID-19 MESHD) is caused by the severe acute respiratory syndrome-coronavirus-2 MESHD (SARS-CoV-2) virus. Some data describing characteristics and prognosis of patients with COVID-19 MESHD and diabetes MESHD are now available, for example for hospitalized patients in the CORONADO study. Potential links between diabetes MESHD and COVID-19 MESHD infection were already described. Indeed Angiotensin-converting-enzyme 2 HGNC ( ACE2 HGNC) has been identified as the receptor for the coronavirus spike protein PROTEIN, and ACE HGNC is expressed on pancreatic beta cells. It was suggested that SARS-CoV2 could induce beta cell damage and new onset diabetes MESHD, but the phenotype of these new cases of diabetes MESHD has not been described.This observation presented in that paper highlights the fact that COVID-19 MESHD infection may also trigger type 1 diabetes MESHD onset. Viral infection MESHD, in particular by enteroviruses but also by coronaviruses, is a well-known environmental trigger for the development of type 1 diabetes MESHD. In the case presented herein, there was a short delay between COVID-19 MESHD infection and diabetes MESHD onset. It remains to determine if the hyperinflammation/cytokine storm described with this infection could accelerate the onset of type 1 diabetes MESHD in genetically susceptible individuals.The relationship between SARS-CoV2 exposition and autoimmune diabetes MESHD development must be further studied, and incidence of type 1 diabetes MESHD will be carefully observed in the next months.

    The Binding Mechanism of Coronavirus Disease 2019 MESHD with Human Angiotensin Converting Enzyme HGNC 2

    Authors: Baliram Lone; Megha Lone

    id:10.20944/preprints202005.0186.v1 Date: 2020-05-11 Source: Preprints.org

    The outbreak across the globe due to coronavirus disease 2019 MESHD ( COVID-19 MESHD) has spread abruptly by infected humans worldwide. The continuous efforts by scientists is on way to understand how pandemic of COVID-19 MESHD resembles and differs from serve acute respiratory syndrome coronavirus (SARS-CoV MESHD) at transcriptomic and genomic level. The SARS-CoV MESHD and COVID-19 MESHD exploits the angiotensin converting enzyme 2 HGNC ( ACE2 HGNC) receptor to gain entry inside the cells.We analyzed the entry COVID-19 MESHD into host cell due to receptor binding domain (RBD) of spike glycoprotein PROTEIN. The proposed simulation data shows similar ternary structures from two viruses shares approximately 80 percent identity in amino acid sequences. Our molecular modeling investigation signifies that angiotensin converting enzyme 2 HGNC ( ACE2 HGNC) has stronger interaction with COVID -19 RBD. The Amino acid phenylaniline F486 LOOP plays vital role due to its penetration into hydrophobic pocket in ACE2 HGNC.The said investigation of S-Glycoprotein PROTEIN RBD of COVID-19 MESHD or SARS-CoV-2 via ACE2 HGNC provides post genome analysis of protein-protein interaction for rapid assessing transmission of infected MESHD patients by deadly CoVID-19 MESHD. The scientific data extracted implies early guidance to control and viral prevention of CoVID-19 MESHD.

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MeSH Disease
HGNC Genes
SARS-CoV-2 Proteins


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