Browse
Submit Data
Databases
API
Help

Dataset Information

32 Views

0 Connections

0 Citations

0 Reanalyses

0 Downloads

Omics score: 0

Computational strategies towards developing novel SARS-CoV-2 M^pro inhibitors against COVID-19.

ABSTRACT: The COVID-19 pandemic caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) remains to be a serious threat due to the lack of a specific therapeutic agent. Computational methods are particularly suitable for rapidly fight against SARS-CoV-2. This present research aims to systematically explore the interaction mechanism of a series of novel bicycloproline-containing SARS-CoV-2 M^pro inhibitors through integrated computational approaches. We designed six structurally modified novel SARS-CoV-2 M^pro inhibitors based on the QSAR study. The four designed compounds with higher docking scores were further explored through molecular docking, molecular dynamics (MD) simulations, free energy calculations, and residual energy contributions estimated by the MM-PBSA approach, with comparison to compound 23(PDB entry 7D3I). This research not only provides robust QSAR models as valuable screening tools for the development of anti-COVID-19 drugs, but also proposes the newly designed SARS-CoV-2 M^pro inhibitors with nanomolar activities that can be potentially used for further characterization to treat SARS-CoV-2 virus.

SUBMITTER: Luo D

PROVIDER: S-EPMC8398673 | biostudies-literature |

REPOSITORIES: biostudies-literature

ACCESS DATA

Json Xml

Similar Datasets

Identification of Mpro inhibitors of SARS-CoV-2 using structure based computational drug repurposing.

Project description:The recent outbreak of COVID-19, caused by the novel pathogen SARS-coronavirus 2 (SARS-CoV-2) is a severe health emergency. In this pandemic, drug repurposing seems to be the most promising alternative to identify effective therapeutic agents for immediate treatment of infected patients. The present study aimed to evaluate all the drugs present in drug bank as potential novel SARS-CoV-2 inhibitors, using computational drug repurposing studies. Docking-based virtual screening and binding energy prediction were performed, followed by Absorption Distribution Metabolism Excretion calculation. Hydroxychloroquine and Nelfinavir have been identified as the best potential inhibitor against the SARS-CoV-2, therefore, they were used as reference compounds in computational DR studies. The docking study revealed 13 best compounds based on their highest binding affinity, binding energy, and dock score concerning the other screened compounds. Out of 13, only 4 compounds were further shortlisted based on their binding energy and best ADME properties. The hierarchical virtual screening yielded the best 04 drugs, DB07042 (compound 2), DB13035 (compound 3), DB13604 (compound 5) and DB08253 (compound 6), with commendable binding energies in kcal/mol, i.e. -65.45, -62.01, -52.09 and -51.70 respectively. Further, Molecular dynamics simulation with 04 best-retrieved hits has confirmed stable trajectories in protein in terms of root mean square deviation and root mean square fluctuation. During 30 ns simulation, the interactions were also found similar to the docking-based studies. However, clinical studies are necessary to investigate their therapeutic use against this outbreak.

| S-EPMC8483991 | biostudies-literature

Identification of SARS-CoV-2 Mpro inhibitors containing P1' 4-fluorobenzothiazole moiety highly active against SARS-CoV-2.

Project description:COVID-19 caused by SARS-CoV-2 has continually been serious threat to public health worldwide. While a few anti-SARS-CoV-2 therapeutics are currently available, their antiviral potency is not sufficient. Here, we identify two orally available 4-fluoro-benzothiazole-containing small molecules, TKB245 and TKB248, which specifically inhibit the enzymatic activity of main protease (Mpro) of SARS-CoV-2 and significantly more potently block the infectivity and replication of various SARS-CoV-2 strains than nirmatrelvir, molnupiravir, and ensitrelvir in cell-based assays employing various target cells. Both compounds also block the replication of Delta and Omicron variants in human-ACE2-knocked-in mice. Native mass spectrometric analysis reveals that both compounds bind to dimer Mpro, apparently promoting Mpro dimerization. X-ray crystallographic analysis shows that both compounds bind to Mpro's active-site cavity, forming a covalent bond with the catalytic amino acid Cys-145 with the 4-fluorine of the benzothiazole moiety pointed to solvent. The data suggest that TKB245 and TKB248 might serve as potential therapeutics for COVID-19 and shed light upon further optimization to develop more potent and safer anti-SARS-CoV-2 therapeutics.

| S-EPMC9958325 | biostudies-literature

SARS-CoV-2 Mpro inhibitors: identification of anti-SARS-CoV-2 Mpro compounds from FDA approved drugs.

Project description:Recent outbreak of COVID-19 pandemic caused by severe acute respiratory syndrome-Coronavirus-2 (SARS-CoV-2) has raised serious global concern for public health. The viral main 3-chymotrypsin-like cysteine protease (Mpro), known to control coronavirus replication and essential for viral life cycle, has been established as an essential drug discovery target for SARS-CoV-2. Herein, we employed computationally screening of Druglib database containing FDA approved drugs against active pocket of SARS-CoV-2 Mpro using MTiopen screen web server, yields a total of 1051 FDA approved drugs with docking energy >-7 kcal/mol. The top 10 screened potential compounds against SARS-CoV-2 Mpro were then studied by re-docking, binding affinity, intermolecular interaction, and complex stability via 100 ns all atoms molecular dynamics (MD) simulation followed by post-simulation analysis, including end point binding free energy, essential dynamics, and residual correlation analysis against native crystal structure ligand N3 inhibitor. Based on comparative molecular simulation and interaction profiling of the screened drugs with SARS-CoV-2 Mpro revealed R428 (-10.5 kcal/mol), Teniposide (-9.8 kcal/mol), VS-5584 (-9.4 kcal/mol), and Setileuton (-8.5 kcal/mol) with stronger stability and affinity than other drugs and N3 inhibitor; and hence, these drugs are advocated for further validation using in vitro enzyme inhibition and in vivo studies against SARS-CoV-2 infection.Communicated by Ramaswamy H. Sarma.

| S-EPMC7651494 | biostudies-literature

Computational investigation of natural compounds as potential main protease (Mpro) inhibitors for SARS-CoV-2 virus.

Project description:The coronavirus disease 2019 (COVID-19) pandemic caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is significantly impacting human lives, overburdening the healthcare system and weakening global economies. Plant-derived natural compounds are being largely tested for their efficacy against COVID-19 targets to combat SARS-CoV-2 infection. The SARS-CoV-2 Main protease (Mpro) is considered an appealing target because of its role in replication in host cells. We curated a set of 7809 natural compounds by combining the collections of five databases viz Dr Duke's Phytochemical and Ethnobotanical database, IMPPAT, PhytoHub, AromaDb and Zinc. We applied a rigorous computational approach to identify lead molecules from our curated compound set using docking, dynamic simulations, the free energy of binding and DFT calculations. Theaflavin and ginkgetin have emerged as better molecules with a similar inhibition profile in both SARS-CoV-2 and Omicron variants.

| S-EPMC9673090 | biostudies-literature

Are vanadium complexes druggable against the main protease Mpro of SARS-CoV-2? - A computational approach.

Project description:In silico techniques helped explore the binding capacities of the SARS-CoV-2 main protease (Mpro) for a series of metalloorganic compounds. Along with small size vanadium complexes a vanadium-containing derivative of the peptide-like inhibitor N3 (N-[(5-methylisoxazol-3-yl)carbonyl]alanyl-l-valyl-N1-((1R,2Z)-4-(benzyloxy)-4-oxo-1-{[(3R)-2-oxopyrrolidin-3-yl] methyl }but-2-enyl)-l-leucinamide) was designed from the crystal structure with PDB entry code 6LU7. On theoretical grounds our consensus docking studies evaluated the binding affinities at the hitherto known binding site of Chymotrypsin-like protease (3CLpro) of SARS-CoV-2 for existing and designed vanadium complexes. This main virus protease (Mpro) has a Cys-His dyad at the catalytic site that is characteristic of metal-dependent or metal-inhibited hydrolases. Mpro was compared to the human protein-tyrosine phosphatase 1B (hPTP1B) with a comparable catalytic dyad. HPTP1B is a key regulator at an early stage in the signalling cascade of the insulin hormone for glucose uptake into cells. The vanadium-ligand binding site of hPTP1B is located in a larger groove on the surface of Mpro. Vanadium constitutes a well-known phosphate analogue. Hence, its study offers possibilities to design promising vanadium-containing binders to SARS-CoV-2. Given the favourable physicochemical properties of vanadium nuclei, such organic vanadium complexes could become drugs not only for pharmacotherapy but also diagnostic tools for early infection detection in patients. This work presents the in silico design of a potential lead vanadium compound. It was tested along with 20 other vanadium-containing complexes from the literature in a virtual screening test by docking to inhibit Mpro of SARS-CoV-2.

| S-EPMC7875704 | biostudies-literature

Recent computational drug repositioning strategies against SARS-CoV-2.

Project description:Since COVID-19 emerged in 2019, significant levels of suffering and disruption have been caused on a global scale. Although vaccines have become widely used, the virus has shown its potential for evading immunities or acquiring other novel characteristics. Whether current drug treatments are still effective for people infected with Omicron remains unclear. Due to the long development cycles and high expense requirements of de novo drug development, many researchers have turned to consider drug repositioning in the search to find effective treatments for COVID-19. Here, we review such drug repositioning and combination efforts towards providing better handling. For potential drugs under consideration, aspects of both structure and function require attention, with specific categories of sequence, expression, structure, and interaction, the key parameters for investigation. For different data types, we show the corresponding differing drug repositioning methods that have been exploited. As incorporating drug combinations can increase therapeutic efficacy and reduce toxicity, we also review computational strategies to reveal drug combination potential. Taken together, we found that graph theory and neural network were the most used strategy with high potential towards drug repositioning for COVID-19. Integrating different levels of data may further improve the success rate of drug repositioning.

| S-EPMC9575573 | biostudies-literature

Computer-aided drug design for the pain-like protease (PLpro) inhibitors against SARS-CoV-2.

Project description:A new coronavirus, known as Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2), is a highly contagious virus and has caused a massive worldwide health crisis. While large-scale vaccination efforts are underway, the management of population health, economic impact and asof-yet unknown long-term effects on physical and mental health will be a key challenge for the next decade. The papain-like protease (PLpro) of SARS-CoV-2 is a promising target for antiviral drugs. This report used pharmacophore-based drug design technology to identify potential compounds as PLpro inhibitors against SARS-CoV-2. The optimal pharmacophore model was fully validated using different strategies and then was employed to virtually screen out 10 compounds with inhibitory. Molecular docking and non-bonding interactions between the targeted protein PLpro and compounds showed that UKR1129266 was the best compound. These results provided a theoretical foundation for future studies of PLpro inhibitors against SARS-CoV-2.

| S-EPMC9841087 | biostudies-literature

Exploration of chalcones as 3-chymotrypsin-like protease (3CLpro) inhibitors of SARS-CoV-2 using computational approaches.

Project description:The main protease 3CLpro is one of the potential targets against coronavirus. Inhibiting this enzyme leads to the interruption of viral replication. Chalcone and its derivatives were reported to possess the ability to bind to 3CLpro protease in the binding pocket. This study explored an in-house database of 269 chalcones as 3CLpro inhibitors using in silico screening models, including molecular docking, molecular dynamics simulation, binding free energy calculation, and ADME prediction. C264 and C235 stand out as the two most potential structures. The top hit compound C264 was with the Jamda score of -2.8329 and the MM/GBSA binding energy mean value of -28.23 ± 3.53 kcal/mol, which was lower than the reference ligand. Despite the lower mean binding energy (-22.07 ± 3.39 kcal/mol), in-depth analysis of binding interaction suggested C235 could be another potential candidate. Further, in vitro and in vivo experiments are required to confirm the inhibitory ability.Supplementary informationThe online version contains supplementary material available at 10.1007/s11224-022-02000-3.

| S-EPMC9253262 | biostudies-literature

Leucoefdin a potential inhibitor against SARS CoV-2 Mpro.

Project description:Leucoefdin an important constituent of various fruits such as banana, raspberry, etc. was explored to target MPro protease of SARS Co-V 2. Ligand was found to bind at active site of MPro with large negative binding energies in molecular docking and simulation study. The docking results showed that Leucoefdin interacted with the MPro by forming hydrogen bonds, at Leu 141, His163, His 164, and Glu 166. Other non-bonded interactions were seen at Met49, Pro52, Tyr54, Phe140, Leu141, Cys145 and Met165. Results of Leucoefdin was in coherence with the recently reported MPro protease-inhibitor complex. It even displayed better binding energies (kcal/mol) in HTVS (-6.28), SP (-7.28), XP (-9.29) and MMGBSA (-44.71) as compared to the reference ligand [HTVS (-4.87), SP (-6.79), XP (-5.75) and MMGBSA (-47.76)]. Leucoefdin-MPro complex on molecular dynamic simulation showed initial fluctuations in RMSD plot for a certain period and attained equilibrium which remained stable during entire simulation for 150 ns. RMSF of protein showed less secondary structure fluctuations and a greater number of H-bond formation with Leucoefdin during 150 ns simulation. Post simulation MMGBSA analysis showed binding energy of -45.98 Kcal/mol. These findings indicated the potential of Leucoefdin as lead compound in R&D for drug discovery and development against SARS CoV-2.Communicated by Ramaswamy H. Sarma.

| S-EPMC7309301 | biostudies-literature

Design, synthesis and biological evaluation of peptidomimetic benzothiazolyl ketones as 3CLpro inhibitors against SARS-CoV-2.

Project description:A series of peptidomimetic compounds containing benzothiazolyl ketone and [2.2.1] azabicyclic ring was designed, synthesized and evaluated in the hope of obtaining potent oral 3CLpro inhibitors with improved pharmacokinetic properties. Among the target compounds, 11b had the best enzymatic potency (IC50 = 0.110 μM) and 11e had the best microsomal stability (t1/2 > 120 min) and good enzyme activity (IC50 = 0.868 μM). Therefore, compounds 11b and 11e were chosen for further evaluation of pharmacokinetics in ICR mice. The results exhibited that the AUC(0-t) of 11e was 5143 h*ng/mL following single-dose oral administration of 20 mg/kg, and the F was 67.98%. Further structural modification was made to obtain compounds 11g-11j based on 11e. Among them, 11j exhibited the best enzyme inhibition activity against SARS-CoV-2 3CLpro (IC50 = 1.646 μM), the AUC(0-t) was 32473 h*ng/mL (20 mg/kg, po), and the F was 48.1%. In addition, 11j displayed significant anti-SARS-CoV-2 activity (EC50 = 0.18 μM) and low cytotoxicity (CC50 > 50 μM) in Vero E6 cells. All of the above results suggested that compound 11j was a promising lead compound in the development of oral 3CLpro inhibitors and deserved further research.

| S-EPMC10204345 | biostudies-literature