Browse
Submit Data
Databases
API
Help

Dataset Information

44 Views

0 Connections

0 Citations

0 Reanalyses

0 Downloads

Omics score: 0

Targeting SARS-CoV-2 Spike Protein/ACE2 Protein-Protein Interactions: a Computational Study.

ABSTRACT: The spike glycoprotein (S) of the SARS-CoV-2 virus surface plays a key role in receptor binding and virus entry. The S protein uses the angiotensin converting enzyme (ACE2) for entry into the host cell and binding to ACE2 occurs at the receptor binding domain (RBD) of the S protein. Therefore, the protein-protein interactions (PPIs) between the SARS-CoV-2 RBD and human ACE2, could be attractive therapeutic targets for drug discovery approaches designed to inhibit the entry of SARS-CoV-2 into the host cells. Herein, with the support of machine learning approaches, we report structure-based virtual screening as an effective strategy to discover PPIs inhibitors from ZINC database. The proposed computational protocol led to the identification of a promising scaffold which was selected for subsequent binding mode analysis and that can represent a useful starting point for the development of new treatments of the SARS-CoV-2 infection.

SUBMITTER: Pirolli D

PROVIDER: S-EPMC8206717 | biostudies-literature | 2021 Jun

REPOSITORIES: biostudies-literature

ACCESS DATA

Json Xml

Publications

Targeting SARS-CoV-2 Spike Protein/ACE2 Protein-Protein Interactions: a Computational Study.

Pirolli Davide D Righino Benedetta B De Rosa Maria Cristina MC

Molecular informatics 20210427 6

The spike glycoprotein (S) of the SARS-CoV-2 virus surface plays a key role in receptor binding and virus entry. The S protein uses the angiotensin converting enzyme (ACE2) for entry into the host cell and binding to ACE2 occurs at the receptor binding domain (RBD) of the S protein. Therefore, the protein-protein interactions (PPIs) between the SARS-CoV-2 RBD and human ACE2, could be attractive therapeutic targets for drug discovery approaches designed to inhibit the entry of SARS-CoV-2 into the ...[more]

PMID: 33904240

Similar Datasets

Implications of SARS-CoV-2 spike protein interactions with Zn-bound form of ACE2: a computational structural study.

Project description:The COVID-19 pandemic has generated a major interest in designing inhibitors to prevent SARS-CoV-2 binding on host cells to protect against infection. One promising approach to such research utilizes molecular dynamics simulation to identify potential inhibitors that can prevent the interaction between spike (S) protein on the virus and angiotensin converting enzyme 2 (ACE2) receptor on the host cells. In these studies, many groups have chosen to exclude the ACE2-bound zinc (Zn) ion, which is critical for its enzymatic activity. While the relatively distant location of Zn ion from the S protein binding site (S1 domain), combined with the difficulties in modeling this ion has motivated the decision of exclusion, Zn can potentially contribute to the structural stability of the entire protein, and thus, may have implications on S protein-ACE2 interaction. In this study, the authors model both the ACE2-S1 and ACE2-inhibitor (mAb) system to investigate if there are variations in structure and the readouts due to the presence of Zn ion. Although distant from the S1 or inhibitor binding region, inclusion/exclusion of Zn has statistically significant effects on the structural stability and binding free energy in these systems. In particular, the binding free energy of the ACE2-S1 and ACE2-inhibitor structures is - 3.26 and - 14.8 kcal/mol stronger, respectively, in the Zn-bound structure than in the Zn-free structures. This finding suggests that including Zn may be important in screening potentially inhibitors and may be particularly important in modeling monoclonal antibodies, which may be more sensitive to changes in antigen structure.

| S-EPMC9891659 | biostudies-literature

mouse ACE2 receptor bound to SARS-CoV-2 variant Beta Spike

Project description: Not available

| EMPIAR-11181 | biostudies-other

SARS-CoV-2 spike protein enhances MAP4K3/GLK-induced ACE2 stability in COVID-19

Project description:ACE2 on epithelial cells is the SARS-CoV-2 entry receptor. Single-cell RNA-sequencing data derived from two COVID-19 cohorts revealed that MAP4K3/GLK-positive epithelial cells were increased in patients. SARS-CoV-2-induced GLK overexpression in epithelial cells correlated with COVID-19 severity and vesicle secretion. GLK overexpression induced the epithelial cell-derived exosomes containing ACE2; the GLK-induced exosomes transported ACE2 proteins to recipient cells, facilitating pseudovirus infection. Consistently, ACE2 proteins were increased in the serum exosomes from another COVID-19 cohort. Remarkably, SARS-CoV-2 spike protein stimulated GLK, and GLK stabilized ACE2 in epithelial cells. Mechanistically, GLK phosphorylated ACE2 at two serine residues (Ser776, Ser783), leading to dissociation of ACE2 from its E3 ligase UBR4. Reduction of UBR4-induced Lys48-linked ubiquitination at three lysine residues (Lys26, Lys112, Lys114) of ACE2 prevented its degradation. Furthermore, SARS-CoV-2 pseudovirus or live virus infection in humanized ACE2 mice induced GLK and ACE2 protein levels, as well as ACE2-containing exosomes. Collectively, ACE2 stabilization by SARS-CoV-2-induced MAP4K3/GLK may contribute to the pathogenesis of COVID-19.

| S-SCDT-EMM-2022-15904 | biostudies-other

Missense variants in human ACE2 modify binding to SARS-CoV-2 Spike

Project description: Not available

| S-BSST649 | biostudies-other

Machine Learning Reveals the Critical Interactions for SARS-CoV-2 Spike Protein Binding to ACE2.

Project description:SARS-CoV and SARS-CoV-2 bind to the human ACE2 receptor in practically identical conformations, although several residues of the receptor-binding domain (RBD) differ between them. Herein, we have used molecular dynamics (MD) simulations, machine learning (ML), and free-energy perturbation (FEP) calculations to elucidate the differences in binding by the two viruses. Although only subtle differences were observed from the initial MD simulations of the two RBD-ACE2 complexes, ML identified the individual residues with the most distinctive ACE2 interactions, many of which have been highlighted in previous experimental studies. FEP calculations quantified the corresponding differences in binding free energies to ACE2, and examination of MD trajectories provided structural explanations for these differences. Lastly, the energetics of emerging SARS-CoV-2 mutations were studied, showing that the affinity of the RBD for ACE2 is increased by N501Y and E484K mutations but is slightly decreased by K417N.

| S-EPMC8204752 | biostudies-literature

SARS-CoV-2 first contact: Spike-ACE2 interactions in COVID-19.

Project description:The full-length human ACE2 in complex with B0 AT1 is anchored to two S in open pre-fusion state which allows establishing pre-invasion interactions with the ACE2 N-terminal domain.

| S-EPMC8239675 | biostudies-literature

Anti-Fungal Drug Anidulafungin Inhibits SARS-CoV-2 Spike-Induced Syncytia Formation by Targeting ACE2-Spike Protein Interaction.

Project description:Drug repositioning continues to be the most effective, practicable possibility to treat COVID-19 patients. The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) virus enters target cells by binding to the ACE2 receptor via its spike (S) glycoprotein. We used molecular docking-based virtual screening approaches to categorize potential antagonists, halting ACE2-spike interactions by utilizing 450 FDA-approved chemical compounds. Three drug candidates (i.e., anidulafungin, lopinavir, and indinavir) were selected, which show high binding affinity toward the ACE2 receptor. The conformational stability of selected docked complexes was analyzed through molecular dynamics (MD) simulations. The MD simulation trajectories were assessed and monitored for ACE2 deviation, residue fluctuation, the radius of gyration, solvent accessible surface area, and free energy landscapes. The inhibitory activities of the selected compounds were eventually tested in-vitro using Vero and HEK-ACE2 cells. Interestingly, besides inhibiting SARS-CoV-2 S glycoprotein induced syncytia formation, anidulafungin and lopinavir also blocked S-pseudotyped particle entry into target cells. Altogether, anidulafungin and lopinavir are ranked the most effective among all the tested drugs against ACE2 receptor-S glycoprotein interaction. Based on these findings, we propose that anidulafungin is a novel potential drug targeting ACE2, which warrants further investigation for COVID-19 treatment.

| S-EPMC8990323 | biostudies-literature

Identification of a short ACE2-derived stapled peptide targeting the SARS-CoV-2 spike protein.

Project description:The design and synthesis of a series of peptide derivatives based on a short ACE2 α-helix 1 epitope and subsequent [i - i+4] stapling of the secondary structure resulted in the identification of a 9-mer peptide capable to compete with recombinant ACE2 towards Spike RBD in the micromolar range. Specifically, SARS-CoV-2 Spike inhibitor screening based on colorimetric ELISA assay and structural studies by circular dichroism showed the ring-closing metathesis cyclization being capable to stabilize the helical structure of the 9-mer 34HEAEDLFYQ42 epitope better than the triazole stapling via click chemistry. MD simulations showed the stapled peptide being able not only to bind the Spike RBD, sterically interfering with ACE2, but also showing higher affinity to the target as compared to parent epitope.

| S-EPMC9842534 | biostudies-literature

mouse ACE2 receptor bound to SARS-CoV-2 variant Omicron BA.2.12.1 Spike

Project description: Not available

| EMPIAR-11180 | biostudies-other

mouse ACE2 receptor bound to SARS-CoV-2 variant Omicron BA.1 Spike

Project description: Not available

| EMPIAR-11179 | biostudies-other