In silico and in vitro evaluation of kaempferol as a potential inhibitor of the SARS-CoV-2 main protease (3CLpro).
Ontology highlight
ABSTRACT:
SUBMITTER: Khan A
PROVIDER: S-EPMC8013176 | biostudies-literature | 2021 Jun
REPOSITORIES: biostudies-literature
Publications
In silico and in vitro evaluation of kaempferol as a potential inhibitor of the SARS-CoV-2 main protease (3CLpro).
Khan Abbas A Heng Wang W Wang Yanjing Y Qiu Jingfei J Wei Xiaoyong X Peng Shaoliang S Saleem Shoaib S Khan Mazhar M Ali Syed Shujait SS Wei Dong-Qing DQ
Phytotherapy research : PTR 20210115 6
Similar Datasets
Project description:Coronavirus main protease (3CLpro), a special cysteine protease in coronavirus family, is highly desirable in the life cycle of coronavirus. Here, molecular docking, ADMET pharmacokinetic profiles and molecular dynamics (MD) simulation were performed to develop specific 3CLpro inhibitor. The results showed that the 137 compounds originated from Chinese herbal have good binding affinity to 3CLpro. Among these, Cleomiscosin C, (+)-Norchelidonine, Protopine, Turkiyenine, Isochelidonine and Mallotucin A possessed prominent drug-likeness properties. Cleomiscosin C and Turkiyenine exhibited excellent pharmacokinetic profiles. Furthermore, the complex of Cleomiscosin C with SARS-CoV-2 main protease presented high stability. The findings in this work indicated that Cleomiscosin C is highly promising as a potential 3CLpro inhibitor, thus facilitating the development of effective drugs for COVID-19.
| S-EPMC10116374 | biostudies-literature
Project description:FB2001 is a drug candidate that targets the main protease of SARS-CoV-2 via covalently binding to cysteine 145. In this study, we evaluated the inhibitory activities of FB2001 against several SARS-CoV-2 variants in vitro and in vivo (in mice), and we also evaluated the histopathological analysis and immunostaining of FB2001 on lung and brain which have been rarely reported. The results showed that FB2001 exhibited potent antiviral efficacy against several current SARS-CoV-2 variants in Vero E6 cells, namely, B.1.1.7 (Alpha): EC50 = 0.39 ± 0.01 μM, EC90 = 0.75 ± 0.01 μM; B.1.351 (Beta): EC50 = 0.28 ± 0.11 μM, EC90 = 0.57 ± 0.21 μM; B.1.617.2 (Delta): EC50 = 0.27 ± 0.05 μM, EC90 = 0.81 ± 0.20 μM; B.1.1.529 (Omicron): EC50 = 0.26 ± 0.06 μM and EC50 = 0.042 ± 0.007 μM (in the presence of a P-glycoprotein inhibitor). FB2001 remained potent against SARS-CoV-2 replication in the presence of high concentrations of human serum, which indicating that human serum had no significant effect on the in vitro inhibitory activity. Additionally, this inhibitor exhibited an additive effect against SARS-CoV-2 when combined with Remdesivir. Furthermore, FB2001 significantly reduced the SARS-CoV-2 copy numbers and titers in the lungs and brains in vivo, and alleviated the pathological symptoms. In addition, FB2001 could alleviated local bleeding, erythrocyte overflow, edema, and inflammatory cell infiltration in brain tissue, and inhibitors reducing viral titers and improving inflammation in the brain have been rarely reported. A physiologically based pharmacokinetic model was established and verified to predict the FB2001 concentration in human lungs. When FB2001 was administered at 200 mg twice a day for 5 days, the observed Ctrough ss in plasma and predicted Ctrough ss of lung total concentration were 0.163 and 2.5 μg/mL, which were approximately 9 and 132-fold higher than the EC50 of 0.019 μg/mL (0.042 μM) against Omicron variant. Taken together, our study suggests that FB2001 is a promising therapeutic agent in COVID-19 treatment and can be combined with remdesivir to achieve improved clinical outcomes. Owing to its good safety and tolerability in healthy human (NCT05197179 and NCT04766931), FB2001 has been approved for Phase II/III clinical trial (NCT05445934).
| S-EPMC9617675 | biostudies-literature
Project description:2-Phenoxyacetamide group has been identified as one of markers in the discovery and development of SARS-CoV-2 antiviral agent through its main protease (Mpro) inhibition pathway. This study aims to study a series of 2-phenoxyacetamide derivatives using in silico method toward SARS-CoV-2 Mpro as the protein target. The study was initiated by employing structure-based pharmacophore to virtually screen and to select the ligands, which have the best fit score (hits) along with the common pharmacophore features being matched. The result shows that from the 11 ligands designed, four ligands are selected as the hits by demonstrating fit score in the range of 56.20 to 65.53 to the pharmacophore model, employing hydrogen bond acceptor (HBA) and hydrophobic (H) as the common features. The hits were then docked into the binding site of the Mpro to see the binding mode of the corresponding hits as well as its affinity. The docking results free energy of binding (ΔGbind) of the hits are in agreement with the pharmacophore fit score, in the range of -6.83 to -7.20 kcal/ mol. To gain the information of the hits as a potential drug to be developed, the in silico study was further proceed by predicting the mutagenic potency, toxicity and pharmacokinetic profiles. Based on the efficiency percentage, all hits meet the criteria as drug candidates by showing 84-88% leading to a conclusion that 2-phenoxyacetamide derivatives are beneficial to be marked as the lead compound for SARS-CoV-2 Mpro inhibitor.
| S-EPMC8666106 | biostudies-literature
Project description:The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the causative agent of COVID-19, is a novel strain of coronavirus first reported in December 2019 which rapidly spread throughout the world and was subsequently declared a pandemic by the World Health Organization (WHO) in March 2020. Although vaccines, as well as treatments, have been rapidly developed and deployed, these are still spread thin, especially in the developing world. There is also a continuing threat of the emergence of mutated variants which may not be as responsive to available vaccines and drugs. Accessible and affordable sources of antiviral drugs against SARS-CoV-2 offer wider options for the clinical treatment of populations at risk for severe COVID-19. Using in silico methods, this study identified potential inhibitors against the SARS-CoV-2 main protease (Mpro), the protease directly responsible for the activation of the viral replication enzyme, from a consolidated database of 1516 Philippine natural products. Molecular docking experiments, along with in silico ADME predictions, determined top ligands from this database with the highest potential inhibitory effects against Mpro. Molecular dynamic trajectories of the apo and diosmetin-7-O-b-D-glucopyranoside (DG) in complex with the protein predicted potential mechanisms of action for the ligand-by separating the Cys145-His41 catalytic dyad and by influencing the protein network through key intra-signaling residues within the Mpro binding site. These findings show the inhibitory potential of DG against the SARS-CoV-2 Mpro, and further validation is recommended through in vitro or in vivo experimentation.
| S-EPMC9540280 | biostudies-literature
Project description:The outbreak of coronavirus disease 2019 (COVID-19) caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) wreaked havoc all over the world. Although vaccines for the disease have recently become available and started to be administered to the population in various countries, there is still a strong and urgent need for treatments to cure COVID-19. One of the safest and fastest strategies is represented by drug repurposing (DRPx). In this study, thirty compounds with known safety profiles were identified from a chemical library of Phase II-and-up compounds through a combination of SOM Biotech's Artificial Intelligence (AI) technology, SOMAIPRO, and in silico docking calculations with third-party software. The selected compounds were then tested in vitro for inhibitory activity against SARS-CoV-2 main protease (3CLpro or Mpro). Of the thirty compounds, three (cynarine, eravacycline, and prexasertib) displayed strong inhibitory activity against SARS-CoV-2 3CLpro. VeroE6 cells infected with SARS-CoV-2 were used to find the cell protection capability of each candidate. Among the three compounds, only eravacycline showed potential antiviral activities with no significant cytotoxicity. A further study is planned for pre-clinical trials.
| S-EPMC9224295 | biostudies-literature
Project description:The continued toll of COVID-19 has halted the smooth functioning of civilization on a global scale. With a limited understanding of all the essential components of viral machinery and the lack of structural information of this new virus, initial drug discovery efforts had limited success. The availability of high-resolution crystal structures of functionally essential SARS-CoV-2 proteins, including 3CLpro, supports the development of target-specific therapeutics. 3CLpro, the main protease responsible for the processing of viral polypeptide, plays a vital role in SARS-CoV-2 viral replication and translation and is an important target in other coronaviruses. Additionally, 3CLpro is the target of repurposed drugs, such as lopinavir and ritonavir. In this study, target proteins were retrieved from the protein data bank (PDB IDs: 6 M03, 6LU7, 2GZ7, 6 W63, 6SQS, 6YB7, and 6YVF) representing different open states of the main protease to accommodate macromolecular substrate. A hydroxyethylamine (HEA) library was constructed from harvested chemical structures from all the series being used in our laboratories for screening against malaria and Leishmania parasites. The database consisted of ∼1000 structure entries, of which 70% were new to ChemSpider at the time of screening. This in-house library was subjected to high throughput virtual screening (HTVS), followed by standard precision (SP) and then extra precision (XP) docking (Schrodinger LLC 2021). The ligand strain and complex energy of top hits were calculated by Molecular Mechanics Generalized Born Surface Area (MM/GBSA) method. Promising hit compounds (n = 40) specifically binding to 3CLpro with high energy and average MM/GBSA scores were then subjected to (100-ns) MD simulations. Using this sequential selection followed by an in-silico validation approach, we found a promising HEA-based compound (N,N'-((3S,3'S)-piperazine-1,4-diylbis(3-hydroxy-1-phenylbutane-4,2-diyl))bis(2-(5-methyl-1,3-dioxoisoindolin-2-yl)-3-phenylpropanamide)), which showed high in vitro antiviral activity against SARS-CoV-2. Further to reduce the size of the otherwise larger ligand, a pharmacophore-based predicted library of ∼42 derivatives was constructed, which were added to the previous compound library and rescreened virtually. Out of several hits from the predicted library, two compounds were synthesized, tested against SARS-CoV-2 culture, and found to have markedly improved antiviral activity.
| S-EPMC8416325 | biostudies-literature
Project description:The Coronavirus Disease 2019 (COVID-19) pandemic caused by the novel lineage B betacoroanvirus severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has resulted in significant mortality, morbidity, and socioeconomic disruptions worldwide. Effective antivirals are urgently needed for COVID-19. The main protease (Mpro) of SARS-CoV-2 is an attractive antiviral target because of its essential role in the cleavage of the viral polypeptide. In this study, we performed an in silico structure-based screening of a large chemical library to identify potential SARS-CoV-2 Mpro inhibitors. Among 8,820 compounds in the library, our screening identified trichostatin A, a histone deacetylase inhibitor and an antifungal compound, as an inhibitor of SARS-CoV-2 Mpro activity and replication. The half maximal effective concentration of trichostatin A against SARS-CoV-2 replication was 1.5 to 2.7µM, which was markedly below its 50% effective cytotoxic concentration (75.7µM) and peak serum concentration (132µM). Further drug compound optimization to develop more stable analogues with longer half-lives should be performed. This structure-based drug discovery platform should facilitate the identification of additional enzyme inhibitors of SARS-CoV-2.
| S-EPMC8071767 | biostudies-literature
Project description:SARS-CoV-2 virus which caused the global pandemic the Coronavirus Disease- 2019 (COVID-2019) has infected about 1,203,959 patients and brought forth death rate about 64,788 among 206 countries as mentioned by WHO in the month of April 2020. The clinical trials are underway for Remdesivir, an investigational anti-viral drug from Gilead Sciences. Antimalarial drugs such as Chloroquine and Hydroxychloroquine derivatives are being used in emergency cases; however, they are not suitable for patients with conditions like diabetes, hypertension and cardiac issues. The lack of availability of approved treatment for this disease calls forth the scientific community to find novel compounds with the ability to treat it. This paper evaluates the compound Andrographolide from Andrographis paniculata as a potential inhibitor of the main protease of SARS-COV-2 (Mpro) through in silico studies such as molecular docking, target analysis, toxicity prediction and ADME prediction. Andrographolide was docked successfully in the binding site of SARS-CoV-2 Mpro. Computational approaches also predicts this molecule to have good solubility, pharmacodynamics property and target accuracy. This molecule also obeys Lipinski's rule, which makes it a promising compound to pursue further biochemical and cell based assays to explore its potential for use against COVID-19.Communicated by Ramaswamy H. Sarma.
| S-EPMC7212536 | biostudies-literature
Project description:The pandemic, due to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has stimulated the search for antivirals to tackle COVID-19 infection. Molecules with known pharmacokinetics and already approved for human use have been demonstrated or predicted to be suitable to be used either directly or as a base for a scaffold-based drug design. Among these substances, quercetin is known to be a potent in vitro inhibitor of 3CLpro, the SARS-CoV-2 main protease. However, its low in vivo bioavailability calls for modifications to its molecular structure. In this work, this issue is addressed by using rutin, a natural flavonoid that is the most common glycosylated conjugate of quercetin, as a model. Combining experimental (spectroscopy and calorimetry) and simulation techniques (docking and molecular dynamics simulations), we demonstrate that the sugar adduct does not hamper rutin binding to 3CLpro, and the conjugated compound preserves a high potency (inhibition constant in the low micromolar range, Ki = 11 μM). Although showing a disruption of the pseudo-symmetry in the chemical structure, a larger steric volume and molecular weight, and a higher solubility compared to quercetin, rutin is able to associate in the active site of 3CLpro, interacting with the catalytic dyad (His41/Cys145). The overall results have implications in the drug-design of quercetin analogs, and possibly other antivirals, to target the catalytic site of the SARS-CoV-2 3CLpro.
| S-EPMC8066963 | biostudies-literature
Project description:The main protease (Mpro) of SARS-CoV-2 is responsible for the cleavage of viral replicase polyproteins 1a and 1ab into their mature form and is highly specific and exclusive in its activity. Many studies have targeted this enzyme by small molecule inhibitors to develop therapeutics against the highly infectious disease Covid-19. Our diet contains many natural antioxidants which along with providing support for proper growth and functioning of the body, pose additional health benefits. Present in-silico analysis depicted that natural antioxidants like sesamin, ellagic acid, capsaisin, and epicatechin along with galangin, exhibited significant binding at the catalytic site of the Mpro enzyme. They interacted with excellent efficiency with the chief active site residue Cys145 and thus seem to possess the remarkable potential to act as drug candidates for the treatment of Covid-19. Such dietary compounds can be easily administered orally with least toxicity related concern and thus yell for urgent exhaustive research to develop into efficient therapies.Communicated by Ramaswamy H. Sarma.
| S-EPMC7484577 | biostudies-literature