scholarly journals Druggability of cavity pockets within SARS-CoV-2 spike glycoprotein and pharmacophore-based drug discovery

2021 ◽  
Author(s):  
Alireza Mohebbi ◽  
Fatemeh Sana Askari ◽  
Ali Salehnia Sammak ◽  
Mohsen Ebrahimi ◽  
Zahra Najafimemar
Keyword(s):  
Drug Discovery ◽  
Viral Entry ◽  
Spike Protein ◽  
Lead Compound ◽  
Autodock Vina ◽  
Spike Glycoprotein ◽  
Viral Glycoprotein ◽  
Chemical Derivatives ◽  
Good Target ◽  
Hit Identification

Aim: Virus spike glycoprotein of SARS-CoV-2 is a good target for drug discovery. Objective: To examine the potential for druggability of spike protein for pharmacophore-based drug discovery and to investigate the binding affinity of natural products with SARS-CoV-2 spike protein. Methods: Druggable cavities were searched though CavityPlus. A pharmacophore was built and used for hit identification. Autodock Vina was used to evaluate the hits' affinities. 10 chemical derivatives were also made from the chemical backbone to optimize the lead compound. Results: 10 druggable cavities were found within the glycoprotein spike. Only one cavity with the highest score at the binding site was selected for pharmacophore extraction. Hit identification resulted in the identification of 410 hits. Discussion: This study provides a druggable region within viral glycoprotein and a candidate compound to block viral entry.

scholarly journals Structural and functional modelling of SARS-CoV-2 entry in animal models

2020 ◽  
Vol 10 (1) ◽  
Author(s):  
Greg N. Brooke ◽  
Filippo Prischi
Keyword(s):  
Animal Models ◽  
Protein Interaction ◽  
Viral Entry ◽  
High Specificity ◽  
Binding Mode ◽  
Transgenic Animal ◽  
Spike Protein ◽  
Binding Modes ◽  
Spike Glycoprotein ◽  
Docking Simulations

Abstract SARS-CoV-2 is the novel coronavirus responsible for the outbreak of COVID-19, a disease that has spread to over 100 countries and, as of the 26th July 2020, has infected over 16 million people. Despite the urgent need to find effective therapeutics, research on SARS-CoV-2 has been affected by a lack of suitable animal models. To facilitate the development of medical approaches and novel treatments, we compared the ACE2 receptor, and TMPRSS2 and Furin proteases usage of the SARS-CoV-2 Spike glycoprotein in human and in a panel of animal models, i.e. guinea pig, dog, cat, rat, rabbit, ferret, mouse, hamster and macaque. Here we showed that ACE2, but not TMPRSS2 or Furin, has a higher level of sequence variability in the Spike protein interaction surface, which greatly influences Spike protein binding mode. Using molecular docking simulations we compared the SARS-CoV and SARS-CoV-2 Spike proteins in complex with the ACE2 receptor and showed that the SARS-CoV-2 Spike glycoprotein is compatible to bind the human ACE2 with high specificity. In contrast, TMPRSS2 and Furin are sufficiently similar in the considered hosts not to drive susceptibility differences. Computational analysis of binding modes and protein contacts indicates that macaque, ferrets and hamster are the most suitable models for the study of inhibitory antibodies and small molecules targeting the SARS-CoV-2 Spike protein interaction with ACE2. Since TMPRSS2 and Furin are similar across species, our data also suggest that transgenic animal models expressing human ACE2, such as the hACE2 transgenic mouse, are also likely to be useful models for studies investigating viral entry.

scholarly journals Structural and functional modelling of SARS-CoV-2 entry in animal models

2020 ◽  
Author(s):  
Greg N. Brooke ◽  
Filippo Prischi
Keyword(s):  
Animal Models ◽  
Protein Interaction ◽  
Viral Entry ◽  
Binding Mode ◽  
Transgenic Animal ◽  
Spike Protein ◽  
Suitable Model ◽  
Binding Modes ◽  
Spike Glycoprotein ◽  
Novel Treatments

Abstract SARS-CoV-2 is the novel coronavirus responsible for the outbreak of COVID-19, a disease that has spread to over 100 countries and, as of the 13 May 2020, has infected over 4 million people. Despite the urgent need to find effective therapeutics, research on SARS-CoV-2 has been affected by a lack of suitable animal models. To facilitate the development of medical approaches and novel treatments, we compared the ACE2 receptor and TMPRSS2 protease usage of the SARS-CoV-2 Spike glycoprotein in human and in a panel of animal models, i.e. guinea pig, dog, cat, rat, rabbit, ferret and mouse. Here we showed that ACE2, but not TMPRSS2, has a higher level of sequence variability in the Spike protein interaction surface, which greatly influences Spike protein binding mode. Comparison of SARS-CoV and SARS-CoV-2 S proteins bound the ACE2 receptors showed that the SARS-CoV-2 Spike glycoprotein has adapted to bind the human, but not rodents, ACE2 with high affinity. In contrast, we did not detect species-specific adaptation for TMPRSS2. Analysis of binding modes and protein contacts indicates that ferrets are the most suitable model for the study of inhibitory antibodies and small molecules targeting the SARS-CoV-2 Spike protein interaction with ACE2. Since TMPRSS2 is similar across species, our data also suggest that transgenic animal models expressing human ACE2, such as the K18-hACE2 mouse, are also likely to be useful models for studies investigating viral entry.

scholarly journals Genetic variants in TMPRSS2 and Structure of SARS-CoV-2 spike glycoprotein and TMPRSS2 complex

2020 ◽  
Author(s):  
Ravikanth Vishnubhotla ◽  
Naveen Vankadari ◽  
Vijayasarathy Ketavarapu ◽  
Ramars Amanchy ◽  
Steffie Avanthi ◽  
...  
Keyword(s):  
Exome Sequencing ◽  
Protease Inhibitors ◽  
Viral Entry ◽  
Genetic Variants ◽  
Spike Protein ◽  
Cleavage Sites ◽  
Spike Glycoprotein ◽  
Whole Exome ◽  
Potential Therapeutics

AbstractSARS-CoV-2, a highly transmittable pathogen has infected over 3.8 million people around the globe. The spike glycoprotein of SARS-CoV-2 engages host ACE2 for adhesion, TMPRSS2 for activation and entry. With the aid of whole-exome sequencing, we report a variant rs12329760 in TMPRSS2 gene and its mutant V160M, which might impede viral entry. Furthermore, we identified TMPRSS2 cleavage sites in S2 domain of spike glycoprotein and report the structure of TMPRSS2 in complex with spike glycoprotein. We also report the structures of protease inhibitors in complex with TMPRSS2, which could hamper the interaction with spike protein. These findings advance our understanding on the role of TMPRSS2 and in the development of potential therapeutics.

scholarly journals Gold Metallodrugs to Fight the Corona Virus: Inhibitory Effects on the SpikeACE2 Interaction and on PLpro Protease Activity by Auranofin and Gold Organometallics

2020 ◽  
Author(s):  
Maria Gil-Moles ◽  
Uttara Basu ◽  
Rolf Büssing ◽  
Henrik Hoffmeister ◽  
Sebastian Türck ◽  
...  
Keyword(s):  
Pilot Study ◽  
Viral Entry ◽  
Drug Targets ◽  
Spike Protein ◽  
Converting Enzyme ◽  
Lead Compound ◽  
Inhibitory Effects ◽  
Gold Complexes ◽  
Angiotensin Converting Enzyme 2 ◽  
Key Enzyme

Gold complexes have a long tradition in medicine and for many examples antirheumatic, anticancer or anti-infective effects have been confirmed. Here we evaluated the lead compound Auranofin and five selected gold organometallics as inhibitors of two relevant drug targets of severe acute respiratory syndrome coronaviruses (SARS-CoV). The gold metallodrugs were effective inhibitors of the interaction of the SARS-CoV-2 spike protein with the angiotensin converting enzyme 2 (ACE2) host receptor and might thus interfere with the viral entry process. The gold metallodrugs were also efficient inhibitors of the SARS-CoV-1 papain-like protease (PLpro), which is a key enzyme in the viral replication. Taken together, the results of this pilot study suggest further evaluation of gold complexes as SARS-CoV antiviral drugs.

scholarly journals Digging for the Discovery of SARS-CoV-2 nsp12 Inhibitors: A Pharmacophore-Based and Molecular Dynamics Simulation Study

2021 ◽  
Author(s):  
Fatemeh Sana Askari ◽  
Mohsen Ebrahimi ◽  
Jabbar Parhiz ◽  
Mina Hassanpour ◽  
Alireza Mohebbi ◽  
...  
Keyword(s):  
Conformational Changes ◽  
High Throughput Screening ◽  
Direct Interaction ◽  
Dynamics Simulation ◽  
Crystallographic Structure ◽  
Lead Compound ◽  
Autodock Vina ◽  
Chemical Library ◽  
Global Threat ◽  
Hit Identification

Abstract Background: The severe acute respiratory syndrome Coronavirus 2 (SARS-CoV-2) is a grave global threat causing Coronavirus Disease 2019 (COVID-19). The therapeutics are urgently needed to cure patients severely infected with COVID-19. The aim of the study was to investigate for potential candidates of nsp12 inhibitors by searching for druggable cavity pockets within the viral protein and drug discovery.Methods: The crystallographic structure of SARS-CoV-2 nsp12 was searched for strong druggable cavity pockets and pharmacophore features by the CavityPlus server. The features were selected for high-throughput screening (HTS) of a chemical library of ZINC natural products and hit identification database by ZINCPharmer. Autodock Vina was furthered utilized for estimation of hits' affinities to nsp12. A lead compound with the highest affinity to nsp12 was simulated dynamically by GROMACS for 10 nanoseconds (ns) to measure the hit stability in complex with nsp12 and conformational changes.Results: 1 of 6 cavities with the highest score was selected for extraction of pharmacophore features and hit-identification. 9 pharmacophores were screened, and a total of unique 1274 hits were identified. One compound, ZINV03977803, with an -11.0 Kcal.mol-1 affinity was selected as the lead compound for molecular dynamic simulation (MDS). The results showed stable interaction between ZINV03977803 and nsp12 during 10 ns of simulation. The room-mean-square of deviation (RMSD) measure showed dramatically high conformational changes in the complex of ZINV03977803 and nsp12 compare two the viral proteins alone.Conclusions: The lead compound ZINV03977803 showed stable interaction with higher potential and hydrogen bonding with the catalytic subunit of SARS-CoV-2, nsp12. It could also inhibit the SARS-CoV-2 life cycle by direct interaction with nsp12 and inhibits RdRp complex formation.

scholarly journals Gold Metallodrugs to Fight the Corona Virus: Inhibitory Effects on the SpikeACE2 Interaction and on PLpro Protease Activity by Auranofin and Gold Organometallics

2020 ◽  
Author(s):  
Maria Gil-Moles ◽  
Uttara Basu ◽  
Rolf Büssing ◽  
Henrik Hoffmeister ◽  
Sebastian Türck ◽  
...  
Keyword(s):  
Pilot Study ◽  
Viral Entry ◽  
Drug Targets ◽  
Spike Protein ◽  
Converting Enzyme ◽  
Lead Compound ◽  
Inhibitory Effects ◽  
Gold Complexes ◽  
Angiotensin Converting Enzyme 2 ◽  
Key Enzyme

Gold complexes have a long tradition in medicine and for many examples antirheumatic, anticancer or anti-infective effects have been confirmed. Here we evaluated the lead compound Auranofin and five selected gold organometallics as inhibitors of two relevant drug targets of severe acute respiratory syndrome coronaviruses (SARS-CoV). The gold metallodrugs were effective inhibitors of the interaction of the SARS-CoV-2 spike protein with the angiotensin converting enzyme 2 (ACE2) host receptor and might thus interfere with the viral entry process. The gold metallodrugs were also efficient inhibitors of the SARS-CoV-1 papain-like protease (PLpro), which is a key enzyme in the viral replication. Taken together, the results of this pilot study suggest further evaluation of gold complexes as SARS-CoV antiviral drugs.

Sitagliptin: a potential drug for the treatment of SARS-CoV-2?

2020 ◽  
Author(s):  
Sanaa Bardaweel
Keyword(s):  
Clinical Trials ◽  
Drug Discovery ◽  
Antimalarial Drug ◽  
Drug Repurposing ◽  
Spike Protein ◽  
Diabetic Patients ◽  
Potential Drug ◽  
Chemokine Production ◽  
Drug Discovery And Development ◽  
Sequence Identity

Recently, an outbreak of fatal coronavirus, SARS-CoV-2, has emerged from China and is rapidly spreading worldwide. As the coronavirus pandemic rages, drug discovery and development become even more challenging. Drug repurposing of the antimalarial drug chloroquine and its hydroxylated form had demonstrated apparent effectiveness in the treatment of COVID-19 associated pneumonia in clinical trials. SARS-CoV-2 spike protein shares 31.9% sequence identity with the spike protein presents in the Middle East Respiratory Syndrome Corona Virus (MERS-CoV), which infects cells through the interaction of its spike protein with the DPP4 receptor found on macrophages. Sitagliptin, a DPP4 inhibitor, that is known for its antidiabetic, immunoregulatory, anti-inflammatory, and beneficial cardiometabolic effects has been shown to reverse macrophage responses in MERS-CoV infection and reduce CXCL10 chemokine production in AIDS patients. We suggest that Sitagliptin may be beneficial alternative for the treatment of COVID-19 disease especially in diabetic patients and patients with preexisting cardiovascular conditions who are already at higher risk of COVID-19 infection.

19F-NMR in Target-based Drug Discovery

2019 ◽  
Vol 26 (26) ◽  
pp. 4964-4983 ◽  
Author(s):  
CongBao Kang
Keyword(s):  
Drug Discovery ◽  
Conformational Changes ◽  
Protein Structures ◽  
19F Nmr ◽  
Binding Affinities ◽  
Protein Ligand Interactions ◽  
Compound Libraries ◽  
Ligand Interactions ◽  
Reference Ligand ◽  
Hit Identification

Solution NMR spectroscopy plays important roles in understanding protein structures, dynamics and protein-protein/ligand interactions. In a target-based drug discovery project, NMR can serve an important function in hit identification and lead optimization. Fluorine is a valuable probe for evaluating protein conformational changes and protein-ligand interactions. Accumulated studies demonstrate that 19F-NMR can play important roles in fragment- based drug discovery (FBDD) and probing protein-ligand interactions. This review summarizes the application of 19F-NMR in understanding protein-ligand interactions and drug discovery. Several examples are included to show the roles of 19F-NMR in confirming identified hits/leads in the drug discovery process. In addition to identifying hits from fluorinecontaining compound libraries, 19F-NMR will play an important role in drug discovery by providing a fast and robust way in novel hit identification. This technique can be used for ranking compounds with different binding affinities and is particularly useful for screening competitive compounds when a reference ligand is available.

scholarly journals The Functional Consequences of the Novel Ribosomal Pausing Site in SARS-CoV-2 Spike Glycoprotein RNA

2021 ◽  
Vol 22 (12) ◽  
pp. 6490
Author(s):  
Olga A. Postnikova ◽  
Sheetal Uppal ◽  
Weiliang Huang ◽  
Maureen A. Kane ◽  
Rafael Villasmil ◽  
...  
Keyword(s):  
Amino Acid ◽  
Insertion Sequence ◽  
Experimental Studies ◽  
Spike Protein ◽  
Spike Glycoprotein ◽  
Furin Cleavage ◽  
New Host ◽  
S Protein ◽  
Furin Cleavage Site ◽  
Ribosome Pausing

The SARS-CoV-2 Spike glycoprotein (S protein) acquired a unique new 4 amino acid -PRRA- insertion sequence at amino acid residues (aa) 681–684 that forms a new furin cleavage site in S protein as well as several new glycosylation sites. We studied various statistical properties of the -PRRA- insertion at the RNA level (CCUCGGCGGGCA). The nucleotide composition and codon usage of this sequence are different from the rest of the SARS-CoV-2 genome. One of such features is two tandem CGG codons, although the CGG codon is the rarest codon in the SARS-CoV-2 genome. This suggests that the insertion sequence could cause ribosome pausing as the result of these rare codons. Due to population variants, the Nextstrain divergence measure of the CCU codon is extremely large. We cannot exclude that this divergence might affect host immune responses/effectiveness of SARS-CoV-2 vaccines, possibilities awaiting further investigation. Our experimental studies show that the expression level of original RNA sequence “wildtype” spike protein is much lower than for codon-optimized spike protein in all studied cell lines. Interestingly, the original spike sequence produces a higher titer of pseudoviral particles and a higher level of infection. Further mutagenesis experiments suggest that this dual-effect insert, comprised of a combination of overlapping translation pausing and furin sites, has allowed SARS-CoV-2 to infect its new host (human) more readily. This underlines the importance of ribosome pausing to allow efficient regulation of protein expression and also of cotranslational subdomain folding.

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