In silico and in vitro evaluation of kaempferol as a potential inhibitor of the SARS-CoV-2 main protease (3CLpro).
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ABSTRACT:
SUBMITTER: Khan A
PROVIDER: S-EPMC8013176 | biostudies-literature |
REPOSITORIES: biostudies-literature
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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: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 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: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 infections (COVID-19) caused by a new type of coronavirus (SARS-CoV-2) have been emerging in the entire world. Therefore, it is necessary to find out potential therapeutic pharmaceuticals for this disease. This study investigates the inhibitory effect of the 3-chymotrypsin-like protease of SARS-CoV-2 (3CLpro) using pharmaceuticals containing ?-ketoamide group and pyridone ring based on molecular docking. Of these, eight pharmaceuticals approved by US-Food and Drug Administration have shown good contact with the catalytic residues of 3CLpro. They are telaprevir, temsirolimus, pimecrolimus, aminoglutethimide, apixaban, buspirone, lenalidomide, and pomalidomide. Their binding affinity score ranged from -5.6 to -7.4 kcal/mol. Hydrogen bonds were observed and reported. To the knowledge, this study report for the first time a compound that could be binding to ALA285, the new residue resulting from genetic modification of 3CLpro of SARS-CoV-2 that has increased its catalytic activity 3.6-fold compared with its predecessor 3CLpro of SARS-CoV. It is recommended that telaprevir, and pyridone-containing pharmaceuticals including aminoglutethimide, apixaban, buspirone, lenalidomide, and pomalidomide be repurposed for COVID-19 treatment after suitable validation and clinical trials.
| S-EPMC7347502 | 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:Structure-based design, synthesis, and biological evaluation of a series of peptidomimetic severe acute respiratory syndrome-coronavirus chymotrypsin-like protease inhibitors are described. These inhibitors were designed and synthesized based upon our X-ray crystal structure of inhibitor 1 bound to SARS-CoV 3CLpro. Incorporation of Boc-Ser as the P(4)-ligand resulted in enhanced SARS-CoV 3CLpro inhibitory activity. Structural analysis of the inhibitor-bound X-ray structure revealed high binding affinity toward the enzyme.
| S-EPMC2112940 | biostudies-other
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
Project description:3CLpro is essential for SARS-CoV-2 replication and infection; its inhibition using small molecules is a potential therapeutic strategy. In this study, a comprehensive crystallography-guided fragment-based drug discovery approach was employed to design new inhibitors for SARS-CoV-2 3CLpro. All small molecules co-crystallized with SARS-CoV-2 3CLpro with structures deposited in the Protein Data Bank were used as inputs. Fragments sitting in the binding pocket (87) were grouped into eight geographical types. They were interactively coupled using various synthetically reasonable linkers to generate larger molecules with divalent binding modes taking advantage of two different fragments' interactions. In total, 1,251 compounds were proposed, and 7,158 stereoisomers were screened using Glide (standard precision and extra precision), AutoDock Vina, and Prime MMGBSA. The top 22 hits having conformations approaching the linear combination of their constituent fragments were selected for MD simulation on Desmond. MD simulation suggested 15 of these did adopt conformations very close to their constituent pieces with far higher binding affinity than either constituent domain alone. These structures could provide a starting point for the further design of SARS-CoV-2 3CLpro inhibitors with improved binding, and structures are provided.
| S-EPMC8444677 | biostudies-literature
Project description:Coronavirus disease 2019 (COVID-19) is a rapidly growing pandemic that requires urgent therapeutic intervention. Finding potential anti COVID-19 drugs aside from approved vaccines is progressively going on. The chemically diverse natural products represent valuable sources for drug leads. In this study, we aimed to find out safe and effective COVID-19 protease inhibitors from a library of natural products which share the main nucleus/skeleton of FDA-approved drugs that were employed in COVID-19 treatment guidelines or repurposed by previous studies. Our library was subjected to virtual screening against SARS-CoV Main protease (Mpro) using Molecular Operating Environment (MOE) software. Twenty-two out of those natural candidates showed higher binding scores compared to their analogues. We repurpose these natural products including alkaloids, glucosinolates, and phenolics as potential platforms for the development of anti-SARS-CoV-2 therapeutics. This study paves the way towards discovering a lead used in the treatment of COVID-19 from natural sources and introduces phytomedicines with dual therapeutic effects against COVID-19 besides their original pharmacological effects. We recommend further in vitro evaluation of their anti-COVID-19 activity and future clinical studies.
| S-EPMC8638226 | biostudies-literature