Browse
Submit Data
Databases
API
Help

Dataset Information

39 Views

0 Connections

0 Citations

0 Reanalyses

0 Downloads

Omics score: 0

Topological analysis of SARS CoV-2 main protease.

ABSTRACT: There is an urgent necessity of effective medication against severe acute respiratory syndrome coronavirus 2 (SARS CoV-2), which is producing the COVID-19 pandemic across the world. Its main protease (M^pro) represents an attractive pharmacological target due to its involvement in essential viral functions. The crystal structure of free M^pro shows a large structural resemblance with the main protease of SARS CoV (nowadays known as SARS CoV-1). Here, we report that average SARS CoV-2 M^pro is 1900% more sensitive than SARS CoV-1 M^pro in transmitting tiny structural changes across the whole protein through long-range interactions. The largest sensitivity of M^pro to structural perturbations is located exactly around the catalytic site Cys-145 and coincides with the binding site of strong inhibitors. These findings, based on a simplified representation of the protein as a residue network, may help in designing potent inhibitors of SARS CoV-2 M^pro.

SUBMITTER: Estrada E

PROVIDER: S-EPMC7286701 | biostudies-literature | 2020 Jun

REPOSITORIES: biostudies-literature

ACCESS DATA

Json Xml

Publications

Topological analysis of SARS CoV-2 main protease.

Estrada Ernesto E

Chaos (Woodbury, N.Y.) 20200601 6

There is an urgent necessity of effective medication against severe acute respiratory syndrome coronavirus 2 (SARS CoV-2), which is producing the COVID-19 pandemic across the world. Its main protease (M<sup>pro</sup>) represents an attractive pharmacological target due to its involvement in essential viral functions. The crystal structure of free M<sup>pro</sup> shows a large structural resemblance with the main protease of SARS CoV (nowadays known as SARS CoV-1). Here, we report that average SA ...[more]

PMID: 32611087

Similar Datasets

Potential SARS-CoV-2 main protease inhibitors.

Project description:The coronavirus disease 2019 (COVID-19) pandemic has prompted an urgent need for new treatment strategies. No target-specific drugs are currently available for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), but new drug candidates targeting the viral replication cycle are being explored. A prime target of drug-discovery efforts is the SARS-CoV-2 main protease (Mpro). The main proteases of different coronaviruses, including SARS-CoV-2, SARS-CoV and Middle East respiratory syndrome coronavirus (MERS-CoV), share a structurally conserved substrate-binding region that can be exploited to design new protease inhibitors. With the recent reporting of the X-ray crystal structure of the SARS-CoV-2 Mpro, studies to discover Mpro inhibitors using both virtual and in vitro screening are progressing rapidly. This review focusses on the recent developments in the search for small-molecule inhibitors targeting the SARS-CoV-2 Mpro.

| S-EPMC7724992 | biostudies-literature

Analysis of the efficacy of HIV protease inhibitors against SARS-CoV-2's main protease.

Project description:BackgroundThe pandemic caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has resulted in millions of infections worldwide. While the search for an effective antiviral is still ongoing, experimental therapies based on repurposing of available antivirals is being attempted, of which HIV protease inhibitors (PIs) have gained considerable interest. Inhibition profiling of the PIs directly against the viral protease has never been attempted in vitro, and while few studies reported an efficacy of lopinavir and ritonavir in SARS-CoV-2 context, the mechanism of action of the drugs remains to be validated.MethodsWe carried out an in-depth analysis of the efficacy of HIV PIs against the main protease of SARS-CoV-2 (Mpro) in cell culture and in vitro enzymatic assays, using a methodology that enabled us to focus solely on any potential inhibitory effects of the inhibitors against the viral protease. For cell culture experiments a dark-to-bright GFP reporter substrate system was designed.ResultsLopinavir, ritonavir, darunavir, saquinavir, and atazanavir were able to inhibit the viral protease in cell culture, albeit in concentrations much higher than their achievable plasma levels, given their current drug formulations. While inhibition by lopinavir was attributed to its cytotoxicity, ritonavir was the most effective of the panel, with IC50 of 13.7 µM. None of the inhibitors showed significant inhibition of SARS-CoV-2 Mpro in our in vitro enzymatic assays up to 100 µM concentration.ConclusionTargeting of SARS-CoV-2 Mpro by some of the HIV PIs might be of limited clinical potential, given the high concentration of the drugs required to achieve significant inhibition. Therefore, given their weak inhibition of the viral protease, any potential beneficial effect of the PIs in COVID-19 context might perhaps be attributed to acting on other molecular target(s), rather than SARS-CoV-2 Mpro.

| S-EPMC7689640 | biostudies-literature

SARS-CoV-2 Main Protease: A Molecular Dynamics Study.

Project description:Herein, we investigate the structure and flexibility of the hydrated SARS-CoV-2 main protease by means of 2.0 μs molecular dynamics (MD) simulations in explicit solvent. After having performed electrostatic pKa calculations on several X-ray structures, we consider both the native (unbound) configuration of the enzyme and its noncovalent complex with a model peptide, Ace-Ala-Val-Leu-Gln∼Ser-Nme, which mimics the polyprotein sequence recognized at the active site. For each configuration, we also study their monomeric and homodimeric forms. The simulations of the unbound systems show that the relative orientation of domain III is not stable in the monomeric form and provide further details about interdomain motions, protomer-protomer interactions, inter-residue contacts, accessibility at the catalytic site, etc. In the presence of the peptide substrate, the monomeric protease exhibits a stable interdomain arrangement, but the relative orientation between the scissile peptide bond and the catalytic dyad is not favorable for catalysis. By means of comparative analysis, we further assess the catalytic impact of the enzyme dimerization, the actual flexibility of the active site region, and other structural effects induced by substrate binding. Overall, our computational results complement previous crystallographic studies on the SARS-CoV-2 enzyme and, together with other simulation studies, should contribute to outline useful structure-activity relationships.

| S-EPMC7409944 | biostudies-literature

The SARS-CoV-2 main protease as drug target.

Project description:The unprecedented pandemic of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is threatening global health. The virus emerged in late 2019 and can cause a severe disease associated with significant mortality. Several vaccine development and drug discovery campaigns are underway. The SARS-CoV-2 main protease is considered a promising drug target, as it is dissimilar to human proteases. Sequence and structure of the main protease are closely related to those from other betacoronaviruses, facilitating drug discovery attempts based on previous lead compounds. Covalently binding peptidomimetics and small molecules are investigated. Various compounds show antiviral activity in infected human cells.

| S-EPMC7331567 | biostudies-literature

Biochemical screening for SARS-CoV-2 main protease inhibitors.

Project description:The Severe Acute Respiratory Syndrome Corona Virus 2 (SARS-CoV-2) pandemic represents a global challenge. SARS-CoV-2's ability to replicate in host cells relies on the action of its non-structural proteins, like its main protease (Mpro). This cysteine protease acts by processing the viruses' precursor polyproteins. As proteases, together with polymerases, are main targets of antiviral drug design, we here have performed biochemical high throughput screening (HTS) with recombinantly expressed SARS-CoV-2 Mpro. A fluorescent assay was used to identify inhibitors in a compound library containing known drugs, bioactive molecules and natural products. These screens led to the identification of 13 inhibitors with IC50 values ranging from 0.2 μM to 23 μM. The screens confirmed several known SARS-CoV Mpro inhibitors as inhibitors of SARS-CoV-2 Mpro, such as the organo-mercuric compounds thimerosal and phenylmercuric acetate. Benzophenone derivatives could also be identified among the most potent screening hits. Additionally, Evans blue, a sulfonic acid-containing dye, could be identified as an Mpro inhibitor. The obtained compounds could be of interest as lead compounds for the development of future SARS-CoV-2 drugs.

| S-EPMC7537881 | biostudies-literature

Insect protease inhibitors; promising inhibitory compounds against SARS-CoV-2 main protease.

Project description:Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the causative agent of coronavirus disease 2019 (COVID-19), has adversely affected global health since its emergence in 2019. The lack of effective treatments prompted worldwide efforts to immediately develop therapeutic strategies against COVID-19. The main protease (Mpro) of SARS-CoV-2 plays a crucial role in viral replication, and therefore it serves as an attractive target for COVID-19-specific drug development. Due to the richness and diversity of insect protease inhibitors, we docked SARS-CoV-2 Mpro onto 25 publicly accessible insect-derived protease inhibitors using the ClusPro server, and the regions with high inhibitory potentials against Mpro were used to design peptides. Interactions of these inhibitory peptides with Mpro were further assessed by two directed docking programs, AutoDock and Haddock. AutoDock analysis predicted the highest binding energy (-9.39 kcal/mol) and the lowest inhibition constant (130 nM) for the peptide 1KJ0-7 derived from SGCI (Schistocerca gregaria chymotrypsin inhibitor). On the other hand, Haddock analysis resulted in the discovery of a different peptide designated 2ERW-9 from infestin, a serine protease inhibitor of Triatoma infestans, with the best docking score (-131), binding energy (-11.7 kcal/mol), and dissociation constant (2.6E-09 M) for Mpro. Furthermore, using molecular dynamic simulations, 1KJ0-7 and 2ERW-9 were demonstrated to form stable complexes with Mpro. The peptides also showed suitable drug-likeness properties compared to commercially available drugs based on Lipinski's rule. Our findings present two peptides with possible protease inhibitor activities against Mpro and further demonstrate the potential of insect-derived peptides and computer-aided methods for drug discovery.

| S-EPMC8755557 | biostudies-literature

Copper(II) Inhibition of the SARS-CoV-2 Main Protease.

Project description:In an analysis of the structural stability of the coronavirus main protease (Mpro), we identified regions of the protein that could be disabled by cobalt(III)-cation binding to histidines and cysteines [1]. Here we have extended our work to include copper(II) chelates, which we have docked to HIS 41 and CYS 145 in the Mpro active-site region. We have found stable docked structures where Cu(II) could readily bond to the CYS 145 thiolate, which would be lethal to the enzyme. We also started studying the Spike Protein, PDB ID: 6VXX and the region around the D614G mutant.

| S-EPMC7668746 | biostudies-literature

Correlation between dissociation and catalysis of SARS-CoV main protease.

Project description:The dimeric interface of severe acute respiratory syndrome coronavirus main protease is a potential target for the anti-SARS drug development. We have generated C-terminal truncated mutants by serial truncations. The quaternary structure of the enzyme was analyzed using both sedimentation velocity and sedimentation equilibrium analytical ultracentrifugation. Global analysis of the combined results showed that truncation of C-terminus from 306 to 300 had no appreciable effect on the quaternary structure, and the enzyme remained catalytically active. However, further deletion of Gln-299 or Arg-298 drastically decreased the enzyme activity to 1-2% of wild type (WT), and the major form was a monomeric one. Detailed analysis of the point mutants of these two amino acid residues and their nearby hydrogen bond partner Ser-123 and Ser-139 revealed a strong correlation between the enzyme activity loss and dimer dissociation.

| S-EPMC7094404 | biostudies-literature

Discovery of novel inhibitors of SARS-CoV-2 main protease.

Project description:Corona Virus Disease 2019 (COVID-19), referred to as 'New Coronary Pneumonia', is a type of acute infectious disease caused by the Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) infection. Mpro is one of the main targets for treating COVID-19. The current research on Mpro mainly focuses on the repurposing of old drugs, and there are only a few novel ligands that inhibit Mpro. In this research, we used computational free energy calculation to screen a compound library against Mpro, and discovered four novel compounds with the two best compounds (AG-690/13507628 and AG-690/13507724) having experimental measured IC50 of just under 3 μM and low cell toxicity. Detailed decomposition of the interactions between the inhibitors and Mpro reveals key interacting residues and interactions that determine the activity. The results from this study should provide a basis for further development of anti-SARS-CoV-2 drugs.Communicated by Ramaswamy H. Sarma.

| S-EPMC8436407 | biostudies-literature

Discovery and Mechanism of SARS-CoV-2 Main Protease Inhibitors.

Project description:The emergence of a new coronavirus, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), presents an urgent public health crisis. Without available targeted therapies, treatment options remain limited for COVID-19 patients. Using medicinal chemistry and rational drug design strategies, we identify a 2-phenyl-1,2-benzoselenazol-3-one class of compounds targeting the SARS-CoV-2 main protease (Mpro). FRET-based screening against recombinant SARS-CoV-2 Mpro identified six compounds that inhibit proteolysis with nanomolar IC50 values. Preincubation dilution experiments and molecular docking determined that the inhibition of SARS-CoV-2 Mpro can occur by either covalent or noncovalent mechanisms, and lead E04 was determined to inhibit Mpro competitively. Lead E24 inhibited viral replication with a nanomolar EC50 value (844 nM) in SARS-CoV-2-infected Vero E6 cells and was further confirmed to impair SARS-CoV-2 replication in human lung epithelial cells and human-induced pluripotent stem cell-derived 3D lung organoids. Altogether, these studies provide a structural framework and mechanism of Mpro inhibition that should facilitate the design of future COVID-19 treatments.

| S-EPMC8491550 | biostudies-literature

OmicsDI is part of the ELIXIR infrastructure

OmicsDI is an Elixir interoperability service. Learn more ›

Tweets

OmicsDI Databases

PRIDE
PeptideAtlas
MassIVE
JPOST Repository
Physiome Model Repository

EGA
EVA
ENA
LINCS
PAXDB
Cell Collective

MetaboLights
Metabolomics Workbench
MetabolomeExpress
GNPS
BioModels
FAIRDOMHub

ArrayExpress
dbGaP
ExpressionAtlas
GEO
NODE

Information

Databases
Help
API
Contact us
Code on GitHub
Terms of use
Submit Data