In silico prediction of the inhibition of new molecules on SARS-CoV-2 3CL protease by using QSAR: PSOSVR approach
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ABSTRACT:
SUBMITTER: Madani A
PROVIDER: S-EPMC10110346 | biostudies-literature | 2023 Apr
REPOSITORIES: biostudies-literature
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Project description:There were severe panics caused by Severe Acute Respiratory Syndrome (SARS) and Middle-East Respiratory Syndrome-Coronavirus. Therefore, researches targeting these viruses have been required. Coronaviruses (CoVs) have been rising targets of some flavonoids. The antiviral activity of some flavonoids against CoVs is presumed directly caused by inhibiting 3C-like protease (3CLpro). Here, we applied a flavonoid library to systematically probe inhibitory compounds against SARS-CoV 3CLpro. Herbacetin, rhoifolin and pectolinarin were found to efficiently block the enzymatic activity of SARS-CoV 3CLpro. The interaction of the three flavonoids was confirmed using a tryptophan-based fluorescence method, too. An induced-fit docking analysis indicated that S1, S2 and S3' sites are involved in binding with flavonoids. The comparison with previous studies showed that Triton X-100 played a critical role in objecting false positive or overestimated inhibitory activity of flavonoids. With the systematic analysis, the three flavonoids are suggested to be templates to design functionally improved inhibitors.
| S-EPMC6882434 | biostudies-literature
Project description:The world has witnessed of many pandemic waves of SARS-CoV-2. However, the incidence of SARS-CoV-2 infection has now declined but the novel variant and responsible cases has been observed globally. Most of the world population has received the vaccinations, but the immune response against COVID-19 is not long-lasting, which may cause new outbreaks. A highly efficient pharmaceutical molecule is desperately needed in these circumstances. In the present study, a potent natural compound that could inhibit the 3CL protease protein of SARS-CoV-2 was found with computationally intensive search. This research approach is based on physics-based principles and a machine-learning approach. Deep learning design was applied to the library of natural compounds to rank the potential candidates. This procedure screened 32,484 compounds, and the top five hits based on estimated pIC50 were selected for molecular docking and modeling. This work identified two hit compounds, CMP4 and CMP2, which exhibited strong interaction with the 3CL protease using molecular docking and simulation. These two compounds demonstrated potential interaction with the catalytic residues His41 and Cys154 of the 3CL protease. Their calculated binding free energies to MMGBSA were compared to those of the native 3CL protease inhibitor. Using steered molecular dynamics, the dissociation strength of these complexes was sequentially determined. In conclusion, CMP4 demonstrated strong comparative performance with native inhibitors and was identified as a promising hit candidate. This compound can be applied in-vitro experiment for the validation of its inhibitory activity. Additionally, these methods can be used to identify new binding sites on the enzyme and to design new compounds that target these sites.
| S-EPMC10104361 | biostudies-literature
Project description:The SARS-CoV-2 3-chymotrypsin-like protease (3CLpro or Mpro) is a key cysteine protease for viral replication and transcription, making it an attractive target for antiviral therapies to combat the COVID-19 disease. Here, we demonstrate that bismuth drug colloidal bismuth subcitrate (CBS) is a potent inhibitor for 3CLpro in vitro and in cellulo. Rather than targeting the cysteine residue at the catalytic site, CBS binds to an allosteric site and results in dissociation of the 3CLpro dimer and proteolytic dysfunction. Our work provides direct evidence that CBS is an allosteric inhibitor of SARS-CoV-2 3CLpro.
| S-EPMC8565384 | biostudies-literature
Project description:The severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) 3CL protease is a promising target for inhibition of viral replication by interaction with a cysteine residue (Cys145) at its catalytic site. Dalcetrapib exerts its lipid-modulating effect by binding covalently to cysteine 13 of a cholesteryl ester transfer protein. Because 12 free cysteine residues are present in the 3CL protease, we investigated the potential of dalcetrapib to inhibit 3CL protease activity and SARS-CoV-2 replication. Molecular docking investigations suggested that dalcetrapib-thiol binds to the catalytic site of the 3CL protease with a delta G value of -8.5 kcal/mol. Dalcetrapib inhibited both 3CL protease activity in vitro and viral replication in Vero E6 cells with IC50 values of 14.4 ± 3.3 μM and an EC50 of 17.5 ± 3.5 μM (mean ± SD). Near-complete inhibition of protease activity persisted despite 1000-fold dilution after ultrafiltration with a nominal dalcetrapib-thiol concentration of approximately 100 times below the IC50 of 14.4 μM, suggesting stable protease-drug interaction. The inhibitory effect of dalcetrapib on the SARS-CoV-2 3CL protease and viral replication warrants its clinical evaluation for the treatment of COVID-19.
| S-EPMC8230949 | biostudies-literature
Project description:The biggest challenge in medical management and control of the COVID-19 pandemic is the nonavailability of the treatment molecules. While vaccines and other biotherapeutic products for managing COVID-19 have reached the market, a small-molecule cure is yet to be developed. This is relevant because the cost of production, storage, and ease of distribution of a small-molecule drug are significantly more favorable than those of biologics. In this paper, we present a multicompound approach, where two drug molecules are administered concurrently to offer an effective therapy for COVID-19. The co-action of the two compounds, each derived from natural origins, has been demonstrated against the 3CL protease, already recognized as a potential drug target for inhibiting SARS-CoV-2. The pair of compounds pursued in this study are flavonoid and naphthalene scaffold. Individually, they offer ∼30 to 35% inhibition at 10 μM. Comprehensive docking and molecular dynamics simulations elucidate that these compounds exhibit excellent binding in the process, which however quickly deteriorates, and the ligand is separated from the binding site. This suggests that while the ligands initially bind with the protease, they are unable to maintain it for an extended period. However, the simulation showed that a simultaneous docked complex of both the compounds together with the protein boosts the stronger binding for a sufficient time. The enzyme assay exhibited 97 and 85% inhibition activity when both compounds were used together at 100 and 50 μM, respectively. Later, a multiconcentration assay was used to determine the coinhibitory activity, and it was observed that the compounds have ∼20 to 30% inhibition activity even at lower concentrations of 0.5 and 1 μM. Surface plasmon resonance was used to measure the binding of the compounds, and when used together, the compounds had a 10-fold greater binding affinity. Thus, the results demonstrate a synergistic mechanism between the two compounds that enhances the inhibition activity against SARS-CoV-2 3CL protease.
| S-EPMC8565457 | biostudies-literature
Project description:BackgroundThe emergence of Coronavirus disease (COVID-19) has been declared a pandemic and made a medical emergency worldwide. Various attempts have been made, including optimizing effective treatments against the disease or developing a vaccine. Since the SARS-CoV-2 protease crystal structure has been discovered, searching for its inhibitors by in silico technique becomes possible.ObjectiveThis study aims to virtually screen the potential of phytoconstituents from the Begonia genus as 3Cl pro-SARS-CoV- 2 inhibitors, based on its crucial role in viral replication, hence making these proteases "promising" for the anti-SARS-CoV-2 target.MethodsIn silico screening was carried out by molecular docking on the web-based program DockThor and validated by a retrospective method. Predictive binding affinity (Dock Score) was used for scoring the compounds. Further molecular dynamics on Desmond was performed to assess the complex stability.ResultsVirtual screening protocol was valid with the area under curve value 0.913. Molecular docking revealed only β-sitosterol- 3-O-β-D-glucopyranoside with a lower docking score of - 9.712 kcal/mol than positive control of indinavir. The molecular dynamic study showed that the compound was stable for the first 30 ns simulations time with Root Mean Square Deviation <3 Å, despite minor fluctuations observed at the end of simulation times. Root Mean Square Fluctuation of catalytic sites HIS41 and CYS145 was 0.756 Å and 0.773 Å, respectively.ConclusionsThis result suggests that β-sitosterol-3-O-β-Dglucopyranoside might be a prospective metabolite compound that can be developed as anti-SARS-CoV-2.
| S-EPMC10365649 | biostudies-literature
Project description:COVID-19 results from SARS-CoV-2, which mutates frequently, challenging current treatments. Therefore, it is critical to develop new therapeutic drugs against this disease. This study explores the interaction between SARS-CoV-2 3CLpro and RetroMAD1, a well-characterized coronavirus protein and potential drug target, using in-silico methods. The analysis through the HDOCK server showed stable complex formation with a binding energy of -12.3, the lowest among reference drugs. The RetroMAD1-3CLpro complex underwent a 100 ns molecular dynamics simulation (MDS) in an explicit solvation system, generating various trajectories, including RMSD, RMSF, hydrogen bonding, radius of gyration, and ligand binding energy. MDS results confirmed intact interactions within the RetroMAD1-3CLpro complex during simulations. In vitro experiments validated RetroMAD1's ability to inhibit 3CLpro enzyme activity and prevent SARS-CoV-2 infection in human bronchial cells. RetroMAD1 exhibited antiviral efficacy comparable to Remdesivir without cytotoxicity at effective concentrations. These results suggest RetroMAD1 as a potential drug candidate against SARS-CoV-2, warranting further in vivo and clinical studies to assess its efficiency.
| S-EPMC10656507 | biostudies-literature
Project description:The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) 3CL protease (3CLpro) has been regarded as an extremely promising antiviral target for the treatment of coronavirus disease 2019 (COVID-19). Here, we carried out a virtual screening based on commercial compounds database to find novel covalent non-peptidomimetic inhibitors of this protease. It allowed us to identify 3 hit compounds with potential covalent binding modes, which were evaluated through an enzymatic activity assay of the SARS-CoV-2 3CLpro. Moreover, an X-ray crystal structure of the SARS-CoV-2 3CLpro in complex with compound 8, the most potent hit with an IC50 value of 8.50 μM, confirmed the covalent binding of the predicted warhead to the catalytic residue C145, as well as portrayed interactions of the compound with S1' and S2 subsites at the ligand binding pocket. Overall, the present work not merely provided an experiment-validated covalent hit targeting the SARS-CoV-2 3CLpro, but also displayed a prime example to seeking new covalent small molecules by a feasible and effective computational approach.
| S-EPMC8783839 | biostudies-literature
Project description:Since the outbreak of the 2019 novel coronavirus disease (COVID-19), the medical research community is vigorously seeking a treatment to control the infection and save the lives of severely infected patients. The main potential candidates for the control of viruses are virally targeted agents. In this short letter, we report our calculations on the inhibitors for the SARS-CoV-2 3CL protease and the spike protein for the potential treatment of COVID-19. The results show that the most potent inhibitors of the SARS-CoV-2 3CL protease include saquinavir, tadalafil, rivaroxaban, sildenafil, dasatinib, etc. Ergotamine, amphotericin b, and vancomycin are most promising to block the interaction of the SARS-CoV-2 S-protein with human ACE-2.
| S-EPMC7357730 | biostudies-literature
Project description:The abundance of polyphenols in edible plants makes them an important component of human nutrition. Considering the ongoing COVID-19 pandemic, a number of studies have investigated polyphenols as bioactive constituents. We applied in-silico molecular docking as well as molecular dynamics supported by in-vitro assays to determine the inhibitory potential of various plant polyphenols against an important SARS-CoV-2 therapeutic target, the protease 3CLpro. Of the polyphenols in initial in-vitro screening, quercetin, ellagic acid, curcumin, epigallocatechin gallate and resveratrol showed IC50 values of 11.8 µM to 23.4 µM. In-silico molecular dynamics simulations indicated stable interactions with the 3CLpro active site over 100 ns production runs. Moreover, surface plasmon resonance spectroscopy was used to measure the binding of polyphenols to 3CLpro in real time. Therefore, we provide evidence for inhibition of SARS-CoV-2 3CLpro by natural plant polyphenols, and suggest further research into the development of these novel 3CLpro inhibitors or biochemical probes.
| S-EPMC8592230 | biostudies-literature