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1.
Results Chem ; 4: 100329, 2022 Jan.
Article in English | MEDLINE | ID: covidwho-2031660

ABSTRACT

This work presented the microwave assisted synthesis of six new 2́-hydroxychalcones and their characterization based on FTIR, UV-Vis, 1H NMR, and mass spectral analysis. Quantum chemical studies confirmed the structures of prepared chalcones. Antioxidant, in vitro antimicrobial and in silico antiviral studies have been performed to evaluate their biological performance. Results of molecular docking of prepared 2́-hydroxychalcones against SARS-CoV-2 (7BQY) main protease disclosed their inhibition which is comparable to standard, remdesivir and better than hydroxychloroquine (HCQ). ADMET prediction revealed them to be non-carcinogenic and relatively safe.

2.
Letters in Organic Chemistry ; 19(11):931-957, 2022.
Article in English | Scopus | ID: covidwho-2029884

ABSTRACT

The novel coronavirus disease (COVID-19) emerged in December 2019. It is caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and is still existent all over the world. Researchers worldwide are continuously conducting in silico studies or virtual screening on various phytochemicals and reporting potential candidates that can be developed against COVID-19 after in vitro and in vivo validation. Antiviral effects of several phytochemicals have been demonstrated against different kinds of coronavirus, including SARS-CoV. Using drug repurposing techniques, a number of phytochemicals have shown substantial antiviral efficacy against COVID 19. This article reviews the efficacy of lead phytochemicals in computational studies on different important targets of SARS-CoV-2 like main protease, ACE-2, papain-like protease, spike protein, nsp-1, nsp-15, RdRp, MTase, helicase, cathepsin, TMPRSS-2. This review discusses potential application of these phytochemicals, which can guide medicinal chemists to choose phytochemicals to proceed with further in vitro and in vivo testing for SARS-CoV-2, which may eventually lead to an effective therapeutic agent and thus can be used to control the current ongoing pandemic. © 2022 Bentham Science Publishers.

3.
SSRN; 2022.
Preprint in English | SSRN | ID: ppcovidwho-343203

ABSTRACT

We report the synthesis of five new Cu(I) acylthiourea complexes (C1-C5) bearing the general formula [Cu(L-R)Cl(PPh3)2] [L = monodentate acylthiourea ligand, R = C6H5 (L1), C6H4CH3(o) (L2), C6H4OCH2CH3(p) (L3), C10H7 (L4) or C6H4Cl(p) (L5)]. All the complexes were characterized by analytical and spectroscopic tools. The complexes (C1-C5) exhibited a distorted tetrahedral geometry as inferred from the single crystal X-ray diffraction study. The complexes were subjected to interaction with biomolecules (calf thymus (CT) DNA/bovine serum albumin (BSA));the one bearing naphthyl substituent (C4) exhibited the highest binding efficacy. Further, anticancer activity of the complexes was studied exclusively against breast cancer cell lines namely MCF7, T47D and MDA MB 231. Complex C4 was found to be highly cytotoxic on the three cancer cell lines with the IC50 values of 0.75, 0.75 and 0.68 µM, respectively. Conveniently, the complexes displayed 4-fold less toxicity against the normal MCF10a human breast cells. Ability of complex C4 to induce apoptosis was analyzed by acridine orange/ethidium bromide (AO/EB) and Hoechst 33258 staining assays. Furthermore, it was found that complex C4 induced apoptosis via reactive oxygen species (ROS)-mediated mitochondrial signaling pathway. Confocal fluorescence images of the cells subjected to lyso and mitotracker staining assays revealed that complex C4 was primarily localized on the mitochondria. Western blot results also confirmed the apoptosis induced by complex C4 in the MDA MB 231 cancer cells. The complexes were also screened for their binding ability with SARS-CoV-2 main protease;interestingly, the complexes exhibited higher binding energy than chloroquine, hydroxychloroquine and remdesivir.

4.
Annals of Phytomedicine-an International Journal ; 10:S77-S85, 2021.
Article in English | Web of Science | ID: covidwho-2026890

ABSTRACT

Viral mutations can become more common as a result of natural selection, random genetic drift or recent epidemiological trends. Even more difficult is to determine whether a single mutation will affect the fate of an illness or a pandemic. World Health Organization designated the latest strain of SARS-CoV-2, the Omicron, as a "variant of concern" as more countries are reporting cases, and it contains a unique mix of mutations that might help it spread faster. Mutations in the SARS-CoV-2 strains at the high rates lead to the in effectiveness of vaccines and developed drugs. As the mutations occur only on the spike proteins of the viral particles, targeting other vital enzymes, i.e., proteases for drug discovery paves way for potential drug candidate irrespective of the mutations. So, the present study focuses on identifying the phytocompounds from Datura metal L. inhibiting the SARS-CoV-2 proteases. The druglikeness, PASS predictions and ADMET properties of the selected compounds were performed. 31 compounds were identified from the KNApSAck database and subjected to molecular docking studies. From the analysis, 7 compounds. Withametelin I, Withametelin J, Withametelin K, Withametelin L, Withametelin M, Withametelin N and Withametelin O showed significant binding energies and ADMET values. Therefore, these compounds can be further utilized for development of novel drugs for treatment of SARS-CoV-2 infections.

5.
Struct Chem ; : 1-21, 2022 Jul 04.
Article in English | MEDLINE | ID: covidwho-2014346

ABSTRACT

COVID-19 disease caused by severe acute respiratory syndrome coronavirus-2 (SARS-CoV2) has resulted in tremendous loss of lives across the world and is continuing to do so. Extensive work is under progress to develop inhibitors which can prevent the disease by arresting the virus in its life cycle. One such way is by targeting the main protease of the virus which is crucial for the cleavage and conversion of polyproteins into functional units of polypeptides. In this endeavor, our effort was to identify hit molecule inhibitors for SARS-CoV2 main protease using fragment-based drug discovery (FBDD), based on the available crystal structure of chromene-based inhibitor (PDB_ID: 6M2N). The designed molecules were validated by molecular docking and molecular dynamics simulations. The stability of the complexes was further assessed by calculating their binding free energies, normal mode analysis, mechanical stiffness, and principal component analysis. Supplementary Information: The online version contains supplementary material available at 10.1007/s11224-022-01995-z.

6.
Med Chem Res ; : 1-10, 2022.
Article in English | Web of Science | ID: covidwho-2014068

ABSTRACT

The rapid development of effective vaccines to combat the SARS-CoV-2 virus has been an effective counter measure to decrease hospitalization and the mortality rate in many countries. However, with the risk of mutated strains decreasing the efficacy of the vaccine, there has been an increasing demand for antivirals to treat COVID-19. While antivirals, such as remdesivir, have had some success treating COVID-19 patients in hospital settings, there is a need for orally bioavailable, cost-effective antivirals that can be administered in outpatient settings to minimize COVID-19-related hospitalizations and death. Nirmatrelvir (PF-07321332) is an orally bioavailable M(pro) (also called 3CL(pro)) inhibitor developed by Pfizer. It is administered in combination with ritonavir, a potent CYP3A4 inhibitor that decreases the metabolism of nirmatrelvir. This review seeks to outline the history of the rational design, the target selectivity, synthesis, drug resistance, and future perspectives of nirmatrelvir. Graphical .

7.
Biochemical and Biophysical Research Communications ; 2022.
Article in English | ScienceDirect | ID: covidwho-2007463

ABSTRACT

Since the onset of the COVID-19 pandemic, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has acquired numerous variations in its intracellular proteins to adapt quickly, become more infectious, and ultimately develop drug resistance by mutating certain hotspot residues. To keep the emerging variants at bay, including Omicron and subvariants, FDA has approved the antiviral nirmatrelvir for mild-to-moderate and high-risk COVID-19 cases. Like other viruses, SARS-CoV-2 could acquire mutations in its main protease (Mpro) to adapt and develop resistance against nirmatrelvir. Employing a unique high-throughput protein design technique, the hotspot residues, and signatures of adaptation of Mpro having the highest probability of mutating and rendering nirmatrelvir ineffective were identified. Our results show that ∼40% of the designed mutations in Mpro already exist in the globally circulating SARS-CoV-2 lineages and several predicted mutations. Moreover, several of the high-frequency, designed mutations were found to be in corroboration with the experimentally reported nirmatrelvir-resistant mutants and are naturally occurring. Our work on the targeted design of the nirmatrelvir-binding site offers a comprehensive picture of potential hotspot sites and resistance mutations in Mpro and is thus crucial in comprehending viral adaptation, robust antiviral design, and surveillance of evolving Mpro variations.

8.
Mol Divers ; 2022 Aug 18.
Article in English | MEDLINE | ID: covidwho-1990719

ABSTRACT

To fight against the devastating coronavirus disease 2019 (COVID-19), identifying robust anti-SARS-CoV-2 therapeutics from all possible directions is necessary. To contribute to this effort, we selected a human metabolites database containing waters and lipid-soluble metabolites to screen against the 3-chymotrypsin-like proteases (3CLpro) protein of SARS-CoV-2. The top 8 hits from virtual screening displayed a docking score varying between ~ - 11 and ~ - 14 kcal/mol. Molecular dynamics simulations complement the virtual screening study in conjunction with the molecular mechanics generalized Born surface area (MM/GBSA) scheme. Our analyses revealed that (HMDB0132640) has the best glide docking score, - 14.06 kcal/mol, and MM-GBSA binding free energy, - 18.08 kcal/mol. The other three lead molecules are also selected along with the top molecule through a critical inspection of their pharmacokinetic properties. HMDB0132640 displayed a better binding affinity than the other three compounds (HMDB0127868, HMDB0134119, and HMDB0125821) due to increased favorable contributions from the intermolecular electrostatic and van der Waals interactions. Further, we have investigated the ligand-induced structural dynamics of the main protease. Overall, we have identified new compounds that can serve as potential leads for developing novel antiviral drugs against SARS-CoV-2 and elucidated molecular mechanisms of their binding to the main protease. Identification of probable hits from human metabolites against SARS-CoV-2 using integrated computational approaches-Missed against MS.

9.
chemRxiv; 2022.
Preprint in English | ChemRxiv | ID: ppcovidwho-341888

ABSTRACT

The search for efficient inhibitors of the SARS-CoV-2 enzymes remains important due to the continuing COVID-19 pandemic. We report the results of computational modeling of the reactions of the SARS-CoV-2 main protease (MPro) with four potential covalent inhibitors. Two of them, carmofur and nirmatrelvir, have been shown experimentally the ability to inhibit MPro. Two other compounds, X77A and X77C, were designed computationally in this work, derived from the structure of X77, a non-covalent inhibitor forming a tight surface complex with MPro. We modified the X77 structure by introducing warheads capable of efficient chemical reactions with the catalytic cysteine residue in the MPro active site. The reactions of the four molecules with MPro were investigated by quantum mechanics/molecular mechanics (QM/MM) calculations. According to calculations, the reactions for all four compounds are exothermic, with sufficiently low barriers, suggesting efficient inhibition of the enzyme. From the chemical perspective, the four compounds react with MPro following three distinct mechanisms. In all cases, the reaction is initiated by a nucleophilic attack of the thiolate group of the deprotonated cysteine residue from the catalytic dyad Cys145-His41 of MPro. In the case of carmofur and X77A, the covalent binding of the thiolate to the ligand involves the formation of the fluoro-uracil leaving group. The reaction with X77C follows the nucleophilic aromatic substitution SNAr mechanism. The reaction of MPro with nirmatrelvir, which has a reactive nitrile group, leads to the formation of the covalent thioimidate adduct with the thiolate of the Cys145 residue in the enzyme active site.

10.
J Biomol Struct Dyn ; : 1-11, 2022 Aug 17.
Article in English | MEDLINE | ID: covidwho-1984726

ABSTRACT

Panduratin A (Pa-A) is a prenylated cyclohexenyl chalcone isolated from the rhizomes of the medicinal and culinary plant Boesenbergia rotunda (L.) Mansf., commonly called fingerroots. Both an ethanolic plant extract and Pa-A have shown a marked antiviral activity against the severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2), responsible for the COVID-19 pandemic disease. Pa-A functions as a protease inhibitor inhibiting infection of human cells by the virus. We have modeled the interaction of Pa-A, and 26 panduratin analogues with the main protease (Mpro) of SARS-CoV-2 using molecular docking. The natural product 4-hydroxypanduratin showed a higher Mpro binding capacity than Pa-A and isopanduratin A. The interaction with MPro of all known panduratin derivatives (Pa-A to Pa-Y) have been compared, together with more than 60 reference products. Three compounds emerged as potential robust MPro binders: Pa-R, Pa-V, Pa-S, with a binding capacity significantly higher than 4-OH-Pa-A and Pa-A. The empirical energy of interaction (ΔE) calculated with the best compound in the panduratin series, Pa-R bound to Mpro, surpassed that measured with the top reference protease inhibitors such a ruprintrivir, lufotrelvir, and glecaprevir. Structure-binding relationships are discussed. Compounds with a flavanone moiety (PA-R/S) are the best binders, better than those with a chromene unit (Pa-F/G). The extended molecules (such as Pa-V) exhibit good Mpro binding, but the dimeric compound Pa-Y is too long and protrudes outside the binding cavity. The work provides novel ideas to guide the design of new molecules interacting with Mpro.Communicated by Ramaswamy H. Sarma.


Panduratin A is the main bioactive molecule in extracts of the medicinal plant Boesenbergia rotunda.Extracts of B. rotunda and Pa-A have shown activity against the virus SARS-CoV-2.We modeled the interaction of 27 panduratin derivatives with the main protease (Mpro) of the virus.Three molecules (Pa-R/V/S) revealed high Mpro binding capacity compared to reference compounds.Structure­binding relationships are discussed, to guide the design of compounds to treat COVID-19.

11.
Eur J Med Chem ; 240: 114596, 2022 Oct 05.
Article in English | MEDLINE | ID: covidwho-1982959

ABSTRACT

Boceprevir is an HCV NSP3 inhibitor that was explored as a repurposed drug for COVID-19. It inhibits the SARS-CoV-2 main protease (MPro) and contains an α-ketoamide warhead, a P1 ß-cyclobutylalanyl moiety, a P2 dimethylcyclopropylproline, a P3 tert-butylglycine, and a P4 N-terminal tert-butylcarbamide. By introducing modifications at all four positions, we synthesized 20 boceprevir-based MPro inhibitors including PF-07321332 and characterized their MPro inhibition potency in test tubes (in vitro) and 293T cells (in cellulo). Crystal structures of MPro bound with 10 inhibitors and cytotoxicity and antiviral potency of 4 inhibitors were characterized as well. Replacing the P1 site with a ß-(S-2-oxopyrrolidin-3-yl)-alanyl (Opal) residue and the warhead with an aldehyde leads to high in vitro potency. The original moieties at P2, P3 and the P4 N-terminal cap positions in boceprevir are better than other tested chemical moieties for high in vitro potency. In crystal structures, all inhibitors form a covalent adduct with the MPro active site cysteine. The P1 Opal residue, P2 dimethylcyclopropylproline and P4 N-terminal tert-butylcarbamide make strong hydrophobic interactions with MPro, explaining high in vitro potency of inhibitors that contain these moieties. A unique observation was made with an inhibitor that contains a P4 N-terminal isovaleramide. In its MPro complex structure, the P4 N-terminal isovaleramide is tucked deep in a small pocket of MPro that originally recognizes a P4 alanine side chain in a substrate. Although all inhibitors show high in vitro potency, they have drastically different in cellulo potency to inhibit ectopically expressed MPro in human 293T cells. In general, inhibitors with a P4 N-terminal carbamide or amide have low in cellulo potency. This trend is reversed when the P4 N-terminal cap is changed to a carbamate. The installation of a P3 O-tert-butyl-threonine improves in cellulo potency. Three molecules that contain a P4 N-terminal carbamate were advanced to cytotoxicity tests on 293T cells and antiviral potency tests on three SARS-CoV-2 variants. They all have relatively low cytotoxicity and high antiviral potency with EC50 values around 1 µM. A control compound with a nitrile warhead and a P4 N-terminal amide has undetectable antiviral potency. Based on all observations, we conclude that a P4 N-terminal carbamate in a boceprevir derivative is key for high antiviral potency against SARS-CoV-2.


Subject(s)
COVID-19 , Carbutamide , Antiviral Agents/chemistry , Antiviral Agents/pharmacology , COVID-19/drug therapy , Carbamates , Humans , Lactams , Leucine , Nitriles , Proline/analogs & derivatives , Protease Inhibitors/chemistry , SARS-CoV-2
12.
Eur J Med Chem ; 238: 114508, 2022 Aug 05.
Article in English | MEDLINE | ID: covidwho-1982957

ABSTRACT

The COVID-19 posed a serious threat to human life and health, and SARS-CoV-2 Mpro has been considered as an attractive drug target for the treatment of COVID-19. Herein, we report 2-(furan-2-ylmethylene)hydrazine-1-carbothioamide derivatives as novel inhibitors of SARS-CoV-2 Mpro developed by in-house library screening and biological evaluation. Similarity search led to the identification of compound F8-S43 with the enzymatic IC50 value of 10.76 µM. Further structure-based drug design and synthetic optimization uncovered compounds F8-B6 and F8-B22 as novel non-peptidomimetic inhibitors of Mpro with IC50 values of 1.57 µM and 1.55 µM, respectively. Moreover, enzymatic kinetic assay and mass spectrometry demonstrated that F8-B6 was a reversible covalent inhibitor of Mpro. Besides, F8-B6 showed low cytotoxicity with CC50 values of more than 100 µM in Vero and MDCK cells. Overall, these novel SARS-CoV-2 Mpro non-peptidomimetic inhibitors provide a useful starting point for further structural optimization.


Subject(s)
COVID-19 , Coronavirus 3C Proteases , Furans , SARS-CoV-2 , Antiviral Agents/chemistry , Antiviral Agents/pharmacology , COVID-19/drug therapy , Coronavirus 3C Proteases/antagonists & inhibitors , Coronavirus 3C Proteases/chemistry , Coronavirus 3C Proteases/metabolism , Drug Discovery/methods , Furans/chemistry , Furans/pharmacology , Humans , Hydrazines/pharmacology , Molecular Docking Simulation , Protease Inhibitors/chemistry , Protease Inhibitors/pharmacology , SARS-CoV-2/drug effects , SARS-CoV-2/enzymology
13.
Comput Biol Med ; 147: 105679, 2022 Aug.
Article in English | MEDLINE | ID: covidwho-1982860

ABSTRACT

Severe acute respiratory syndrome coronavirus 2 was originally identified in Wuhan city of China in December 2019 and it spread rapidly throughout the globe, causing a threat to human life. Since targeted therapies are deficient, scientists all over the world have an opportunity to develop novel drug therapies to combat COVID-19. After the declaration of a global medical emergency, it was established that the Food and Drug Administration (FDA) could permit the use of emergency testing, treatments, and vaccines to decrease suffering, and loss of life, and restore the nation's health and security. The FDA has approved the use of remdesivir and its analogs as an antiviral medication, to treat COVID-19. The primary protease of SARS-CoV-2, which has the potential to regulate coronavirus proliferation, has been a viable target for the discovery of medicines against SARS-CoV-2. The present research deals with the in silico technique to screen phytocompounds from a traditional medicinal plant, Bauhinia variegata for potential inhibitors of the SARS-CoV-2 main protease. Dried leaves of the plant B. variegata were used to prepare aqueous and methanol extract and the constituents were analyzed using the GC-MS technique. A total of 57 compounds were retrieved from the aqueous and methanol extract analysis. Among these, three lead compounds (2,5 dimethyl 1-H Pyrrole, 2,3 diphenyl cyclopropyl methyl phenyl sulphoxide, and Benzonitrile m phenethyl) were shown to have the highest binding affinity (-5.719 to -5.580 kcal/mol) towards SARS-CoV-2 Mpro. The post MD simulation results also revealed the favorable confirmation and stability of the selected lead compounds with Mpro as per trajectory analysis. The Prime MM/GBSA binding free energy supports this finding, the top lead compound 2,3 diphenyl cyclopropyl methyl phenyl sulphoxide showed high binding free energy (-64.377 ± 5.24 kcal/mol) towards Mpro which reflects the binding stability of the molecule with Mpro. The binding free energy of the complexes was strongly influenced by His, Gln, and Glu residues. All of the molecules chosen are found to have strong pharmacokinetic characteristics and show drug-likeness properties. The lead compounds present acute toxicity (LD50) values ranging from 670 mg/kg to 2500 mg/kg; with toxicity classifications of 4 and 5 classes. Thus, these compounds could behave as probable lead candidates for treatment against SARS-CoV-2. However further in vitro and in vivo studies are required for the development of medication against SARS-CoV-2.


Subject(s)
Bauhinia , COVID-19 , Bauhinia/metabolism , COVID-19/drug therapy , Gas Chromatography-Mass Spectrometry , Humans , Methanol , Molecular Docking Simulation , Molecular Dynamics Simulation , Protease Inhibitors/chemistry , Protease Inhibitors/pharmacology , SARS-CoV-2 , Viral Nonstructural Proteins/chemistry
14.
Biochem Biophys Res Commun ; 616: 8-13, 2022 08 06.
Article in English | MEDLINE | ID: covidwho-1982607

ABSTRACT

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) provoked a pandemic of acute respiratory disease, namely coronavirus disease 2019 (COVID-19). Currently, effective drugs for this disease are urgently warranted. Anisodamine is a traditional Chinese medicine that is predicted as a potential therapeutic drug for the treatment of COVID-19. Therefore, this study aimed to investigate its antiviral activity and crucial targets in SARS-CoV-2 infection. SARS-CoV-2 and anisodamine were co-cultured in Vero E6 cells, and the antiviral activity of anisodamine was assessed by immunofluorescence assay. The antiviral activity of anisodamine was further measured by pseudovirus entry assay in HEK293/hACE2 cells. Finally, the predictions of crucial targets of anisodamine on SARS-CoV-2 were analyzed by molecular docking studies. We discovered that anisodamine suppressed SARS-CoV-2 infection in Vero E6 cells, and reduced the SARS-CoV-2 pseudovirus entry to HEK293/hACE2 cells. Furthermore, molecular docking studies indicated that anisodamine may target SARS-CoV-2 main protease (Mpro) with the docking score of -6.63 kcal/mol and formed three H-bonds with Gly143, Cys145, and Cys44 amino acid residues at the predicted active site of Mpro. This study suggests that anisodamine is a potent antiviral agent for treating COVID-19.


Subject(s)
COVID-19 , Coronavirus 3C Proteases , SARS-CoV-2 , Solanaceous Alkaloids , Antiviral Agents/chemistry , Antiviral Agents/pharmacology , COVID-19/drug therapy , COVID-19/virology , Coronavirus 3C Proteases/antagonists & inhibitors , Coronavirus 3C Proteases/drug effects , Coronavirus 3C Proteases/metabolism , HEK293 Cells , Humans , Molecular Docking Simulation , Peptide Hydrolases , Protease Inhibitors/pharmacology , Solanaceous Alkaloids/pharmacology , Viral Nonstructural Proteins/chemistry
15.
French-Ukrainian Journal of Chemistry ; 10(1):30-47, 2022.
Article in English | Web of Science | ID: covidwho-1976330

ABSTRACT

The recent outbreak of coronavirus disease 2019 (COVID-19) is posing a global threat to human population. The pandemic caused by novel coronavirus (2019-nCoV), also called as severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2);first emerged in Wuhan city, Hubei province of China in December 2019. The rapid human to human transmission has caused the contagion to spread world-wide affecting 244,385,444 (244.4 million) people globally causing 4,961,489 (5 million) fatalities dated by 27 October 2021. At present, 6,697,607,393 (6.7 billion) vaccine doses have been administered dated by 27 October 2021, for the prevention of COVID-19 infections. Even so, this critical and threatening situation of pandemic and due to various variants' emergence, the pandemic control has become challenging;this calls for gigantic efforts to find new potent drug candidates and effective therapeutic approaches against the virulent respiratory disease of COVID-19. In the respiratory morbidities of COVID-19, the functionally crucial drug target for the antiviral treatment could be the main protease/3-chymotrypsin protease (Mpro/3CLpro) enzyme that is primarily involved in viral maturation and replication. In view of this, in the current study I have designed a library of small molecules against the main protease (Mpro) of coronavirus SARS-CoV-2 (2019-nCoV) by using multimodal generative neural-networks. The scaffold-based molecular docking of the series of compounds at the active site of the protein was performed;binding poses of the molecules were evaluated and protein-ligand interaction studies followed by the binding affinity calculations validated the findings. I have identified a number of small promising lead compounds that could serve as potential inhibitors of the main protease (Mpro) enzyme of coronavirus SARS-CoV-2 (2019-nCoV). This study would serve as a step forward in the development of effective antiviral therapeutic agents against the COVID-19.

16.
Molecules ; 27(15)2022 Aug 01.
Article in English | MEDLINE | ID: covidwho-1969393

ABSTRACT

Siddha medicine is one of the oldest medical systems in the world and is believed to have originated more than 10,000 years ago and is prevalent across ancient Tamil land. It is undeniable that inhibitor preferences rise with increasing solubility in water due to the considerations pertaining to the bioavailability and the ease of which unabsorbed residues can be disposed of. In this study, we showed the phytochemical discrimination of Saussurea costus extracted with water at room temperature as a green extraction procedure. A total of 48 compounds were identified using gas chromatography-mass spectrometry (GC-MS). The fatty acids had a high phytochemical abundance at 73.8%, followed by tannins at 8.2%, carbohydrates at 6.9%, terpenoids at 4.3%, carboxylic acids at 2.5%, hydrocarbons at 2.4%, phenolic compounds at 0.2%, and sterols at 1.5%. Of these compounds, 22 were docked on the active side and on the catalytic dyad of His41 and Cys145 of the main protease of SARS-CoV-2 (Mpro). Eight active inhibitors were carbohydrates, five were fatty acids, three were terpenoids, two were carboxylic acids, one was a tannin, one was a phenolic compound, and one was a sterol. The best inhibitors were 4,8,13-Cyclotetradecatriene-1,3-diol, 1,5,9-trimethyl-12-(1-methylethyl), Andrographolide, and delta.4-Androstene-3.beta.,17.beta.-diol, with a binding affinity that ranged from -6.1 kcal/mol to -6.5 kcal/mol. The inhibitory effect of Saussurea costus of SARS-CoV-2 entry into the cell was studied using a pseudovirus with Spike proteins from the D614G variant and the VOC variants Gamma and Delta. Based on the viral cycle of SARS-CoV-2, our results suggest that the Saussurea costus aqueous extract has no virucidal effect and inhibits the virus in the events after cell entry. Furthermore, the biological activity of the aqueous extract was investigated against HSV-1 virus and two bacterial strains, namely Staphylococcus aureus ATCC BAA 1026 and Escherichia coli ATCC 9637. According to this study, an enormous number of water-soluble inhibitors were identified from Saussurea costus against the Mpro, and this is unprecedented as far as we know.


Subject(s)
COVID-19 , Saussurea , COVID-19/drug therapy , Carbohydrates , Carboxylic Acids , Fatty Acids , Humans , India , Molecular Docking Simulation , Molecular Dynamics Simulation , Peptide Hydrolases/metabolism , Phytochemicals/pharmacology , Protease Inhibitors/chemistry , SARS-CoV-2 , Saussurea/chemistry , Terpenes , Water
17.
Int J Mol Sci ; 23(15)2022 Jul 29.
Article in English | MEDLINE | ID: covidwho-1969295

ABSTRACT

Among a group of 310 natural antiviral natural metabolites, our team identified three compounds as the most potent natural inhibitors against the SARS-CoV-2 main protease (PDB ID: 5R84), Mpro. The identified compounds are sattazolin and caprolactin A and B. A validated multistage in silico study was conducted using several techniques. First, the molecular structures of the selected metabolites were compared with that of GWS, the co-crystallized ligand of Mpro, in a structural similarity study. The aim of this study was to determine the thirty most similar metabolites (10%) that may bind to the Mpro similar to GWS. Then, molecular docking against Mpro and pharmacophore studies led to the choice of five metabolites that exhibited good binding modes against the Mpro and good fit values against the generated pharmacophore model. Among them, three metabolites were chosen according to ADMET studies. The most promising Mpro inhibitor was determined by toxicity and DFT studies to be caprolactin A (292). Finally, molecular dynamics (MD) simulation studies were performed for caprolactin A to confirm the obtained results and understand the thermodynamic characteristics of the binding. It is hoped that the accomplished results could represent a positive step in the battle against COVID-19 through further in vitro and in vivo studies on the selected compounds.


Subject(s)
COVID-19 , SARS-CoV-2 , Antiviral Agents/chemistry , Antiviral Agents/pharmacology , COVID-19/drug therapy , Coronavirus 3C Proteases , Cysteine Endopeptidases/metabolism , Humans , Molecular Docking Simulation , Molecular Dynamics Simulation , Protease Inhibitors/chemistry , Viral Nonstructural Proteins/metabolism
18.
Struct Chem ; : 1-18, 2022 Aug 01.
Article in English | MEDLINE | ID: covidwho-1966169

ABSTRACT

The novel coronavirus 2019 (COVID-19) caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has spread rapidly worldwide, and new drug treatments for COVID-19 are urgently required. To find the potential inhibitors against the main protease (Mpro) of SARS-CoV-2, we investigated the inhibitory potential of naturally occurring compounds from the plants Moringa oleifera, Aloe vera, and Nyctanthes arbor-tristis, using molecular docking, classical molecular mechanics optimizations, and ab initio fragment molecular orbital (FMO) calculations. Of the 35 compounds that we simulated, feralolide from Aloe vera exhibited the highest binding affinity against Mpro. Therefore, we proposed novel compounds based on the feralolide and investigated their binding properties to Mpro. The FMO results indicated that the introduction of a hydroxyl group into feralolide significantly enhances its binding affinity to Mpro. These results provide useful information for developing potent Mpro inhibitors. Supplementary Information: The online version contains supplementary material available at 10.1007/s11224-022-02021-y.

19.
Elife ; 112022 07 26.
Article in English | MEDLINE | ID: covidwho-1964559

ABSTRACT

Analyzing how mutations affect the main protease of SARS-CoV-2 may help researchers develop drugs that are effective against current and future variants of the virus.


Subject(s)
COVID-19 , Antiviral Agents/pharmacology , Antiviral Agents/therapeutic use , COVID-19/drug therapy , Coronavirus 3C Proteases , Cysteine Endopeptidases , Humans , Molecular Docking Simulation , Protease Inhibitors , SARS-CoV-2 , Viral Nonstructural Proteins
20.
Int J Mol Sci ; 23(13)2022 Jun 21.
Article in English | MEDLINE | ID: covidwho-1963998

ABSTRACT

In continuation of our antecedent work against COVID-19, three natural compounds, namely, Luteoside C (130), Kahalalide E (184), and Streptovaricin B (278) were determined as the most promising SARS-CoV-2 main protease (Mpro) inhibitors among 310 naturally originated antiviral compounds. This was performed via a multi-step in silico method. At first, a molecular structure similarity study was done with PRD_002214, the co-crystallized ligand of Mpro (PDB ID: 6LU7), and favored thirty compounds. Subsequently, the fingerprint study performed with respect to PRD_002214 resulted in the election of sixteen compounds (7, 128, 130, 156, 157, 158, 180, 184, 203, 204, 210, 237, 264, 276, 277, and 278). Then, results of molecular docking versus Mpro PDB ID: 6LU7 favored eight compounds (128, 130, 156, 180, 184, 203, 204, and 278) based on their binding affinities. Then, in silico toxicity studies were performed for the promising compounds and revealed that all of them have good toxicity profiles. Finally, molecular dynamic (MD) simulation experiments were carried out for compounds 130, 184, and 278, which exhibited the best binding modes against Mpro. MD tests revealed that luteoside C (130) has the greatest potential to inhibit SARS-CoV-2 main protease.


Subject(s)
COVID-19 , Antiviral Agents/chemistry , Antiviral Agents/pharmacology , COVID-19/drug therapy , Cysteine Endopeptidases/metabolism , Humans , Molecular Docking Simulation , Molecular Dynamics Simulation , Peptide Hydrolases/metabolism , Protease Inhibitors/chemistry , Protease Inhibitors/pharmacology , SARS-CoV-2 , Viral Nonstructural Proteins/metabolism
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