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1.
Int J Mol Sci ; 23(4)2022 Feb 21.
Article in English | MEDLINE | ID: covidwho-1705083

ABSTRACT

We theoretically investigated the adsorption of two common anti-COVID drugs, favipiravir and chloroquine, on fluorinated C60 fullerene, decorated with metal ions Cr3+, Fe2+, Fe3+, Ni2+. We focused on the effect of fluoridation on the interaction of fullerene with metal ions and drugs in an aqueous solution. We considered three model systems, C60, C60F2 and C60F48, and represented pristine, low-fluorinated and high-fluorinated fullerenes, respectively. Adsorption energies, deformation of fullerene and drug molecules, frontier molecular orbitals and vibrational spectra were investigated in detail. We found that different drugs and different ions interacted differently with fluorinated fullerenes. Cr3+ and Fe2+ ions lead to the defluorination of low-fluorinated fullerenes. Favipiravir also leads to their defluorination with the formation of HF molecules. Therefore, fluorinated fullerenes are not suitable for the delivery of favipiravir and similar drugs molecules. In contrast, we found that fluorine enhances the adsorption of Ni2+ and Fe3+ ions on fullerene and their activity to chloroquine. Ni2+-decorated fluorinated fullerenes were found to be stable and suitable carriers for the loading of chloroquine. Clear shifts of infrared, ultraviolet and visible spectra can provide control over the loading of chloroquine on Ni2+-doped fluorinated fullerenes.


Subject(s)
Amides/chemistry , Antiviral Agents/chemistry , Chloroquine/chemistry , Fullerenes/chemistry , Metals/chemistry , Pyrazines/chemistry , COVID-19 , Density Functional Theory , Drug Carriers/chemistry , Drug Delivery Systems , Halogenation , Models, Molecular , Nickel/chemistry
2.
J Mol Model ; 28(3): 64, 2022 Feb 18.
Article in English | MEDLINE | ID: covidwho-1699453

ABSTRACT

This paper is a summary of research that looks at the potential of fullerene-like (MO)12 nanoclusters (NCs) in drug-carrying systems using density functional theory. Favipiravir/Zn12O12 (- 34.80 kcal/mol), Favipiravir/Mg12O12 (- 34.98 kcal/mol), and Favipiravir/Be12O12 (- 30.22 kcal/mol) were rated in order of drug adsorption degrees. As a result, Favipiravir attachment to (MgO)12 and (ZnO)12 might be simple, increasing Favipiravir loading efficiency. In addition, the quantum theory of atoms in molecules (QTAIM) assessment was utilized to look at the interactions between molecules. The FMO, ESP, NBO, and Eads reactivity patterns were shown to be in excellent agreement with the QTAIM data. The electrostatic properties of the system with the biggest positive charge on the M atom and the largest Eads were shown to be the best. This system was shown to be the best attraction site for nucleophilic agents. The findings show that (MgO)12 and (ZnO)12 have great carrier potential and may be used in medication delivery.


Subject(s)
Amides/administration & dosage , Amides/chemistry , Antiviral Agents/administration & dosage , Drug Delivery Systems/methods , Nanostructures/chemistry , Pyrazines/administration & dosage , Pyrazines/chemistry , Antiviral Agents/chemistry , COVID-19/drug therapy , Density Functional Theory , Fullerenes/chemistry , Humans , Nanostructures/administration & dosage , Quantum Theory , Spectrophotometry, Ultraviolet , Static Electricity
3.
Sci Rep ; 11(1): 23465, 2021 12 06.
Article in English | MEDLINE | ID: covidwho-1556248

ABSTRACT

Human coronavirus NL63 (HCoV-NL63) mainly affects young children and immunocompromised patients, causing morbidity and mortality in a subset of patients. Since no specific treatment is available, this study aims to explore the anti-SARS-CoV-2 agents including favipiravir and remdesivir for treating HCoV-NL63 infection. We first successfully modelled the 3D structure of HCoV-NL63 RNA-dependent RNA polymerase (RdRp) based on the experimentally solved SARS-CoV-2 RdRp structure. Molecular docking indicated that favipiravir has similar binding affinities to SARS-CoV-2 and HCoV-NL63 RdRp with LibDock scores of 75 and 74, respectively. The LibDock scores of remdesivir to SARS-CoV-2 and HCoV-NL63 were 135 and 151, suggesting that remdesivir may have a higher affinity to HCoV-NL63 compared to SARS-CoV-2 RdRp. In cell culture models infected with HCoV-NL63, both favipiravir and remdesivir significantly inhibited viral replication and production of infectious viruses. Overall, remdesivir compared to favipiravir is more potent in inhibiting HCoV-NL63 in cell culture. Importantly, there is no evidence of resistance development upon long-term exposure to remdesivir. Furthermore, combining favipiravir or remdesivir with the clinically used antiviral cytokine interferon-alpha resulted in synergistic effects. These findings provided a proof-of-concept that anti-SARS-CoV-2 drugs, in particular remdesivir, have the potential to be repurposed for treating HCoV-NL63 infection.


Subject(s)
Adenosine Monophosphate/analogs & derivatives , Alanine/analogs & derivatives , Amides/chemistry , Antiviral Agents/chemistry , Coronavirus NL63, Human/enzymology , Pyrazines/chemistry , RNA-Dependent RNA Polymerase/chemistry , Adenosine Monophosphate/chemistry , Adenosine Monophosphate/metabolism , Adenosine Monophosphate/pharmacology , Alanine/chemistry , Alanine/metabolism , Alanine/pharmacology , Amides/metabolism , Amides/pharmacology , Animals , Antiviral Agents/metabolism , Antiviral Agents/pharmacology , Binding Sites , Cell Culture Techniques , Cell Line , Coronavirus NL63, Human/physiology , Haplorhini , Humans , Molecular Docking Simulation , Pyrazines/metabolism , Pyrazines/pharmacology , RNA-Dependent RNA Polymerase/metabolism , Virus Replication/drug effects
4.
Int J Mol Sci ; 22(21)2021 Oct 21.
Article in English | MEDLINE | ID: covidwho-1480798

ABSTRACT

Disseminated intravascular coagulation (DIC) is a severe condition characterized by the systemic formation of microthrombi complicated with bleeding tendency and organ dysfunction. In the last years, it represents one of the most frequent consequences of coronavirus disease 2019 (COVID-19). The pathogenesis of DIC is complex, with cross-talk between the coagulant and inflammatory pathways. The objective of this study is to investigate the anti-inflammatory action of ultramicronized palmitoylethanolamide (um-PEA) in a lipopolysaccharide (LPS)-induced DIC model in rats. Experimental DIC was induced by continual infusion of LPS (30 mg/kg) for 4 h through the tail vein. Um-PEA (30 mg/kg) was given orally 30 min before and 1 h after the start of intravenous infusion of LPS. Results showed that um-PEA reduced alteration of coagulation markers, as well as proinflammatory cytokine release in plasma and lung samples, induced by LPS infusion. Furthermore, um-PEA also has the effect of preventing the formation of fibrin deposition and lung damage. Moreover, um-PEA was able to reduce the number of mast cells (MCs) and the release of its serine proteases, which are also necessary for SARS-CoV-2 infection. These results suggest that um-PEA could be considered as a potential therapeutic approach in the management of DIC and in clinical implications associated to coagulopathy and lung dysfunction, such as COVID-19.


Subject(s)
Amides/therapeutic use , Blood Coagulation Disorders/drug therapy , Disseminated Intravascular Coagulation/drug therapy , Ethanolamines/therapeutic use , Palmitic Acids/therapeutic use , Sepsis/complications , Amides/chemistry , Amides/pharmacology , Animals , Blood Coagulation Disorders/etiology , COVID-19/pathology , COVID-19/virology , Cytokines/blood , Cytokines/metabolism , Disease Models, Animal , Disseminated Intravascular Coagulation/etiology , Ethanolamines/chemistry , Ethanolamines/pharmacology , Fibrin Fibrinogen Degradation Products/metabolism , Lipopolysaccharides/toxicity , Lung/metabolism , Lung/pathology , Male , Mast Cells/cytology , Mast Cells/drug effects , Mast Cells/metabolism , Palmitic Acids/chemistry , Palmitic Acids/pharmacology , Partial Thromboplastin Time , Prothrombin Time , Rats , Rats, Sprague-Dawley , SARS-CoV-2/isolation & purification , Sepsis/pathology , Serine Proteases/metabolism
5.
Int J Mol Sci ; 22(20)2021 Oct 15.
Article in English | MEDLINE | ID: covidwho-1470891

ABSTRACT

SARS-CoV-2, or severe acute respiratory syndrome coronavirus 2, represents a new pathogen from the family of Coronaviridae that caused a global pandemic of COVID-19 disease. In the absence of effective antiviral drugs, research of novel therapeutic targets such as SARS-CoV-2 RNA-dependent RNA polymerase (RdRp) becomes essential. This viral protein is without a human counterpart and thus represents a unique prospective drug target. However, in vitro biological evaluation testing on RdRp remains difficult and is not widely available. Therefore, we prepared a database of commercial small-molecule compounds and performed an in silico high-throughput virtual screening on the active site of the SARS-CoV-2 RdRp using ensemble docking. We identified a novel thioether-amide or guanidine-linker class of potential RdRp inhibitors and calculated favorable binding free energies of representative hits by molecular dynamics simulations coupled with Linear Interaction Energy calculations. This innovative procedure maximized the respective phase-space sampling and yielded non-covalent inhibitors representing small optimizable molecules that are synthetically readily accessible, commercially available as well as suitable for further biological evaluation and mode of action studies.


Subject(s)
Antiviral Agents/chemistry , Enzyme Inhibitors/chemistry , RNA-Dependent RNA Polymerase/antagonists & inhibitors , SARS-CoV-2/enzymology , Viral Proteins/antagonists & inhibitors , Amides/chemistry , Antiviral Agents/metabolism , Antiviral Agents/therapeutic use , Binding Sites , COVID-19/drug therapy , COVID-19/virology , Catalytic Domain , Databases, Chemical , Drug Design , Enzyme Inhibitors/metabolism , Enzyme Inhibitors/therapeutic use , Guanidine/chemistry , Humans , Molecular Docking Simulation , Molecular Dynamics Simulation , RNA-Dependent RNA Polymerase/metabolism , SARS-CoV-2/isolation & purification , Structure-Activity Relationship , Sulfides/chemistry , Thermodynamics , Viral Proteins/metabolism
6.
Biochemistry ; 59(48): 4601-4608, 2020 12 08.
Article in English | MEDLINE | ID: covidwho-1387100

ABSTRACT

The development of reliable ways of predicting the binding free energies of covalent inhibitors is a challenge for computer-aided drug design. Such development is important, for example, in the fight against the SARS-CoV-2 virus, in which covalent inhibitors can provide a promising tool for blocking Mpro, the main protease of the virus. This work develops a reliable and practical protocol for evaluating the binding free energy of covalent inhibitors. Our protocol presents a major advance over other approaches that do not consider the chemical contribution of the binding free energy. Our strategy combines the empirical valence bond method for evaluating the reaction energy profile and the PDLD/S-LRA/ß method for evaluating the noncovalent part of the binding process. This protocol has been used in the calculations of the binding free energy of an α-ketoamide inhibitor of Mpro. Encouragingly, our approach reproduces the observed binding free energy. Our study of covalent inhibitors of cysteine proteases indicates that in the choice of an effective warhead it is crucial to focus on the exothermicity of the point on the free energy surface of a peptide cleavage that connects the acylation and deacylation steps. Overall, we believe that our approach should provide a powerful and effective method for in silico design of covalent drugs.


Subject(s)
Amides/chemistry , Amides/pharmacology , Peptide Hydrolases/metabolism , Protease Inhibitors/chemistry , Protease Inhibitors/pharmacology , SARS-CoV-2/enzymology , Amides/metabolism , Molecular Docking Simulation , Peptide Hydrolases/chemistry , Protease Inhibitors/metabolism , Protein Binding , Protein Conformation , SARS-CoV-2/drug effects , Thermodynamics
7.
Angew Chem Int Ed Engl ; 59(45): 20154-20160, 2020 11 02.
Article in English | MEDLINE | ID: covidwho-1384106

ABSTRACT

Phosphoramidates composed of an amino acid and a nucleotide analogue are critical metabolites of prodrugs, such as remdesivir. Hydrolysis of the phosphoramidate liberates the nucleotide, which can then be phosphorylated to become the pharmacologically active triphosphate. Enzymatic hydrolysis has been demonstrated, but a spontaneous chemical process may also occur. We measured the rate of enzyme-free hydrolysis for 17 phosphoramidates of ribonucleotides with amino acids or related compounds at pH 7.5. Phosphoramidates of proline hydrolyzed fast, with a half-life time as short as 2.4 h for Pro-AMP in ethylimidazole-containing buffer at 37 °C; 45-fold faster than Ala-AMP and 120-fold faster than Phe-AMP. Crystal structures of Gly-AMP, Pro-AMP, ßPro-AMP and Phe-AMP bound to RNase A as crystallization chaperone showed how well the carboxylate is poised to attack the phosphoramidate, helping to explain this reactivity. Our results are significant for the design of new antiviral prodrugs.


Subject(s)
Amides/metabolism , Amino Acids/chemistry , Nucleotides/metabolism , Phosphoric Acids/metabolism , Adenosine Monophosphate/analogs & derivatives , Adenosine Monophosphate/chemistry , Adenosine Monophosphate/metabolism , Alanine/analogs & derivatives , Alanine/chemistry , Alanine/metabolism , Amides/chemistry , Antiviral Agents/chemistry , Antiviral Agents/metabolism , Antiviral Agents/pharmacology , COVID-19/drug therapy , COVID-19/pathology , COVID-19/virology , Catalytic Domain , Crystallography, X-Ray , Half-Life , Hydrogen-Ion Concentration , Hydrolysis , Kinetics , Molecular Dynamics Simulation , Nucleotides/chemistry , Phosphoric Acids/chemistry , Ribonuclease, Pancreatic/chemistry , Ribonuclease, Pancreatic/metabolism , SARS-CoV-2/drug effects , SARS-CoV-2/isolation & purification
8.
Molecules ; 26(13)2021 Jun 28.
Article in English | MEDLINE | ID: covidwho-1383893

ABSTRACT

The work is devoted to the study of the complementarity of the electronic structures of the ligands and SARS-CoV-2 RNA-dependent RNA polymerase. The research methodology was based on determining of 3D maps of electron densities of complexes using an original quantum free-orbital AlteQ approach. We observed a positive relationship between the parameters of the electronic structure of the enzyme and ligands. A complementarity factor of the enzyme-ligand complexes has been proposed. The console applications of the AlteQ complementarity assessment for Windows and Linux (alteq_map_enzyme_ligand_4_win.exe and alteq_map_enzyme_ligand_4_linux) are available for free at the ChemoSophia webpage.


Subject(s)
Coronavirus RNA-Dependent RNA Polymerase/chemistry , Electrons , SARS-CoV-2/enzymology , Algorithms , Amides/chemistry , Antiviral Agents/chemistry , Ligands , Molecular Structure , Protein Binding , Pyrazines/chemistry , Ribonucleosides/chemistry
9.
Virol J ; 18(1): 146, 2021 07 13.
Article in English | MEDLINE | ID: covidwho-1309916

ABSTRACT

BACKGROUND: Favipiravir is used in treatment of Covid-19 patients. We aimed to share of ocular surface fluorescence in a patient after Favipiravir treatment in this case report. CASE PRESENTATION: A 20-year-old male patient declared no known systemic disease prior to Covid-19. He applied to us with blurry vision and blue light reflection after Covid-19 treatment with Favipiravir. We observed bilateral fluorescence on his eyes and fluorescence of his nails. Biomicroscopic examination was insignificant. CONCLUSION: We investigated the fluorescence of favipiravir tablets under ultraviolet light. Drug demonstrated fluorescence. We recorded the favipiravir fluorescence in-vitro. This appears to be a strong evidence in terms of the linkage between the fluorescence of the ocular surface and favipiravir.


Subject(s)
Amides/adverse effects , Antiviral Agents/adverse effects , COVID-19/drug therapy , Eye/chemistry , Pyrazines/adverse effects , Adult , Amides/administration & dosage , Amides/chemistry , Antiviral Agents/administration & dosage , Antiviral Agents/chemistry , COVID-19/virology , Eye/virology , Fluorescence , Humans , Male , Pyrazines/administration & dosage , Pyrazines/chemistry , SARS-CoV-2/physiology
10.
Mol Pharm ; 18(8): 3108-3115, 2021 08 02.
Article in English | MEDLINE | ID: covidwho-1305357

ABSTRACT

Coronavirus disease 2019 (COVID-19) has spread across the world, and no specific antiviral drugs have yet been approved to combat this disease. Favipiravir (FAV) is an antiviral drug that is currently in clinical trials for use against COVID-19. However, the delivery of FAV is challenging because of its limited solubility, and its formulation is difficult with common organic solvents and water. To address these issues, four FAV ionic liquids (FAV-ILs) were synthesized as potent antiviral prodrugs and were fully characterized by nuclear magnetic resonance (NMR) spectroscopy, Fourier-transform infrared (FT-IR) spectrometry, powder X-ray diffraction (PXRD), thermogravimetric analysis (TGA), derivative thermogravimetry (DTG), and differential scanning calorimetry (DSC). The aqueous solubility and in vivo pharmacokinetic properties of the FAV-ILs were also evaluated. The FAV-ILs exhibited improved aqueous solubility by 78 to 125 orders of magnitude when compared with that of free FAV. Upon oral dosing in mice, the absolute bioavailability of the ß-alanine ethyl ester FAV formulation was increased 1.9-fold compared with that of the control FAV formulation. The peak blood concentration, elimination half-life, and mean absorption time of FAV were also increased by 1.5-, 2.0-, and 1.5-fold, respectively, compared with the control. Furthermore, the FAV in the FAV-ILs exhibited significantly different biodistribution compared with the control FAV formulation. Interestingly, drug accumulation in the lungs and liver was improved 1.5-fold and 1.3-fold, respectively, compared with the control FAV formulation. These results indicate that the use of ILs exhibits potential as a simple, scalable strategy to improve the solubility and oral absorption of hydrophobic drugs, such as FAV.


Subject(s)
Amides/administration & dosage , Antiviral Agents/administration & dosage , Ionic Liquids/chemistry , Pyrazines/administration & dosage , Administration, Oral , Amides/chemical synthesis , Amides/chemistry , Amides/pharmacokinetics , Animals , COVID-19/drug therapy , Female , Mice , Mice, Inbred BALB C , Pyrazines/chemical synthesis , Pyrazines/chemistry , Pyrazines/pharmacokinetics , Solubility , Tissue Distribution
11.
Molecules ; 26(12)2021 Jun 16.
Article in English | MEDLINE | ID: covidwho-1282539

ABSTRACT

Furan-2-carboxylic acid was used as a starting material for the synthesis of dehydro-homopilopic acid. Esterification, hydrogenation and enzymatic hydrolysis followed by the reduction of Weinreb amides and a single-step attachment of a 1-methyl-imidazole residue allowed for the concise synthesis of both enantiomers of pilocarpine.


Subject(s)
4-Butyrolactone/analogs & derivatives , Furans/chemistry , Pilocarpine/chemical synthesis , 4-Butyrolactone/chemical synthesis , Amides/chemistry , Carboxylic Acids/chemistry , Esterification , Hydrogenation , Hydrolysis , Pilocarpine/chemistry , Stereoisomerism
12.
Magn Reson Chem ; 59(7): 746-751, 2021 07.
Article in English | MEDLINE | ID: covidwho-1182204

ABSTRACT

Favipiravir is an established antiviral that is currently being assessed as an investigational drug for the treatment of COVID-19. Favipiravir is strikingly similar to two molecules that the World Health Organization (WHO) lists as essential medicines, which also consist of a six-membered aromatic N-heterocycle bearing a carboxamide function: the anti-tuberculosis agent, pyrazinamide, and nicotinamide, also known as vitamin B3 . We demonstrate the utility of 1 H nuclear magnetic resonance (NMR) profiling, an emerging pharmacopoeial tool, for the highly specific identification, selective differentiation of congeners, and subsequent detection of drug falsification or adulteration of these medicines. The straightforward comparison of basic 1-D 1 H NMR spectra, obtained with benchtop or advanced NMR instruments alike, offers a rapid identity assay and works independently of physical reference materials. This approach accelerates and advances pharmaceutical quality control measures under situations of increased drug demand and altered economy, such as during a pandemic.


Subject(s)
Amides/analysis , Antiviral Agents/analysis , Drug Contamination/prevention & control , Niacinamide/analysis , Pyrazinamide/analysis , Pyrazines/analysis , Quality Control , Amides/chemistry , Antiviral Agents/chemistry , Niacinamide/chemistry , Proton Magnetic Resonance Spectroscopy , Pyrazinamide/chemistry , Pyrazines/chemistry , World Health Organization
13.
Anal Chim Acta ; 1159: 338418, 2021 May 15.
Article in English | MEDLINE | ID: covidwho-1172409

ABSTRACT

Favipiravir, a promising antiviral agent, is undergoing clinical trials for the potential treatment of the novel coronavirus disease 2019 (COVID-19). This is the first report for the electrochemical activity of favipiravir and its electroanalytical sensing. For this purpose, the effect of cationic surfactant, CTAB was demonstrated on the enhanced accumulation of favipiravir at the surface of cathodically pretreated boron-doped diamond (CPT-BDD) electrode. At first, the electrochemical properties of favipiravir were investigated in the surfactant-free solutions by the means of cyclic voltammetry. The compound presented a single oxidation step which is irreversible and adsorption controlled. A systematic study of various operational conditions, such as electrode pretreatment, pH of the supporting electrolyte, concentration of CTAB, accumulation variables, and instrumental parameters on the adsorptive stripping response, was examined using square-wave voltammetry. An oxidation signal at around +1.21 V in Britton-Robinson buffer at pH 8.0 containing 6 × 10-4 M CTAB allowed to the adsorptive stripping voltammetric determination of favipiravir (after 60 s accumulation step at open-circuit condition). The process could be used in the concentration range with two linear segments of 0.01-0.1 µg mL-1 (6.4 × 10-8-6.4 × 10-7 M) and 0.1-20.0 µg mL-1 (6.4 × 10-7-1.3 × 10-4 M). The limit of detection values were found to be 0.0028 µg mL-1 (1.8 × 10-8 M), and 0.023 µg mL-1 (1.5 × 10-7 M) for the first and second segments of calibration graph, respectively. The feasibility of developed methodology was tested to the analysis of the commercial tablet formulations and model human urine samples.


Subject(s)
Amides/chemistry , Antiviral Agents/chemistry , Boron , Diamond , Electrodes , Pyrazines/chemistry , Surface-Active Agents/chemistry , Humans , SARS-CoV-2/drug effects
14.
J Org Chem ; 86(7): 5065-5072, 2021 04 02.
Article in English | MEDLINE | ID: covidwho-1139704

ABSTRACT

Currently, remdesivir is the first and only FDA-approved antiviral drug for COVID-19 treatment. Adequate supplies of remdesivir are highly warranted to cope with this global public health crisis. Herein, we report a Weinreb amide approach for preparing the key intermediate of remdesivir in the glycosylation step where overaddition side reactions are eliminated. Starting from 2,3,5-tri-O-benzyl-d-ribonolactone, the preferred route consisting of three sequential steps (Weinreb amidation, O-TMS protection, and Grignard addition) enables a high-yield (65%) synthesis of this intermediate at a kilogram scale. In particular, the undesirable PhMgCl used in previous methods was successfully replaced by MeMgBr. This approach proved to be suitable for the scalable production of the key remdesivir intermediate.


Subject(s)
Adenosine Monophosphate/analogs & derivatives , Alanine/analogs & derivatives , Amides/chemistry , Antiviral Agents/chemical synthesis , Adenosine Monophosphate/chemical synthesis , Alanine/chemical synthesis
15.
Phys Chem Chem Phys ; 23(11): 6746-6757, 2021 Mar 21.
Article in English | MEDLINE | ID: covidwho-1132112

ABSTRACT

COVID-19, the disease caused by the newly discovered coronavirus-SARS-CoV-2, has created a global health, social, and economic crisis. As of mid-January 2021, there are over 90 million confirmed cases and more than 2 million reported deaths due to COVID-19. Currently, there are very limited therapeutics for the treatment or prevention of COVID-19. For this reason, it is important to find drug targets that will lead to the development of safe and effective therapeutics against the disease. The main protease (Mpro) of the virus is an attractive target for the development of effective antiviral therapeutics because it is required for proteolytic cleavage of viral polyproteins. Furthermore, the Mpro has no human homologues, so drugs designed to bind to this target directly have less risk for off-target effects. Recently, several high-resolution crystallographic structures of the Mpro in complex with inhibitors have been determined-to guide drug development and to spur efforts in structure-based drug design. One of the primary objectives of modern structure-based drug design is the accurate prediction of receptor-ligand binding affinities for rational drug design and discovery. Here, we perform rigorous alchemical absolute binding free energy calculations and QM/MM calculations to give insight into the total binding energy of two recently crystallized inhibitors of SARS-CoV-2 Mpro, namely, N3 and α-ketoamide 13b. The total binding energy consists of both covalent and non-covalent binding components since both compounds are covalent inhibitors of the Mpro. Our results indicate that the covalent and non-covalent binding free energy contributions of both inhibitors to the Mpro target differ significantly. The N3 inhibitor has more favourable non-covalent interactions, particularly hydrogen bonding, in the binding site of the Mpro than the α-ketoamide inhibitor. Also, the Gibbs energy of reaction for the Mpro-N3 covalent adduct is greater than the Gibbs reaction energy for the Mpro-α-ketoamide covalent adduct. These differences in the covalent and non-covalent binding free energy contributions for both inhibitors could be a plausible explanation for their in vitro differences in antiviral activity. Our findings are consistent with the reversible and irreversible character of both inhibitors as reported by experiment and highlight the importance of both covalent and non-covalent binding free energy contributions to the absolute binding affinity of a covalent inhibitor towards its target. This information could prove useful in the rational design, discovery, and evaluation of potent SARS-CoV-2 Mpro inhibitors for targeted antiviral therapy.


Subject(s)
Peptidomimetics/chemistry , Protease Inhibitors/chemistry , SARS-CoV-2/enzymology , Viral Matrix Proteins/antagonists & inhibitors , Amides/chemistry , Amides/metabolism , Binding Sites , COVID-19/pathology , COVID-19/virology , Catalytic Domain , Drug Design , Humans , Hydrogen-Ion Concentration , Kinetics , Ligands , Molecular Dynamics Simulation , Peptidomimetics/metabolism , Protease Inhibitors/metabolism , Quantum Theory , SARS-CoV-2/isolation & purification , Thermodynamics , Viral Matrix Proteins/metabolism
16.
Proc Natl Acad Sci U S A ; 118(7)2021 02 16.
Article in English | MEDLINE | ID: covidwho-1060504

ABSTRACT

The RNA polymerase inhibitor favipiravir is currently in clinical trials as a treatment for infection with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), despite limited information about the molecular basis for its activity. Here we report the structure of favipiravir ribonucleoside triphosphate (favipiravir-RTP) in complex with the SARS-CoV-2 RNA-dependent RNA polymerase (RdRp) bound to a template:primer RNA duplex, determined by electron cryomicroscopy (cryoEM) to a resolution of 2.5 Å. The structure shows clear evidence for the inhibitor at the catalytic site of the enzyme, and resolves the conformation of key side chains and ions surrounding the binding pocket. Polymerase activity assays indicate that the inhibitor is weakly incorporated into the RNA primer strand, and suppresses RNA replication in the presence of natural nucleotides. The structure reveals an unusual, nonproductive binding mode of favipiravir-RTP at the catalytic site of SARS-CoV-2 RdRp, which explains its low rate of incorporation into the RNA primer strand. Together, these findings inform current and future efforts to develop polymerase inhibitors for SARS coronaviruses.


Subject(s)
Amides/pharmacology , Coronavirus RNA-Dependent RNA Polymerase/metabolism , Enzyme Inhibitors/pharmacology , Pyrazines/pharmacology , SARS-CoV-2/ultrastructure , Amides/chemistry , Coronavirus RNA-Dependent RNA Polymerase/antagonists & inhibitors , Coronavirus RNA-Dependent RNA Polymerase/chemistry , Cryoelectron Microscopy/methods , Enzyme Inhibitors/chemistry , Pyrazines/chemistry , Ribonucleotides/chemistry , SARS-CoV-2/drug effects , SARS-CoV-2/enzymology , Single Molecule Imaging/methods
17.
Spectrochim Acta A Mol Biomol Spectrosc ; 247: 119082, 2021 Feb 15.
Article in English | MEDLINE | ID: covidwho-1023740

ABSTRACT

With the global epidemic of the COVID-19 virus, extensive and rapid research on drug therapy is underway around the world. In this regard, one of the most widely studied drugs is Favipiravir. Our aim in this paper is to conduct comprehensive research based on the Density Functional Theory (DFT) on the potential of metallofullerenes as suitable drug carriers. The surface interaction of Favipiravir with organometallic compound resulted by doping of the five transition metals of the first row of the periodic table (Ti, Cr, Cr, Fe, Ni, and Zn) was examined in depth to select the most suitable metallofullerenes. First, the adsorption geometries of Favipiravir drug onto each metallofullerene were deeply investigated. It was found that Cr-, Fe-, and Ni-doped fullerenes provide the excellent adsorbent property with adsorption energies of -148.2, -149.6, and -146.6 kJ/mol, respectively. The Infrared spectroscopy (IR) study was conducted to survey the stretching vibration of bonds involving in the systems, specialty the CO in the drug, CM in the metallofullerene, and MO in the metallofullerene-drug complex. Finally, the UV-vis analysis showed that the absorption spectra for the studied systems may be attributed to the transition from π-π* and/or n-π*.


Subject(s)
Amides/chemistry , COVID-19/epidemiology , Fullerenes/chemistry , Pandemics , Pyrazines/chemistry , SARS-CoV-2/chemistry , Amides/therapeutic use , COVID-19/drug therapy , Fullerenes/therapeutic use , Humans , Molecular Structure , Pyrazines/therapeutic use , Spectrophotometry, Infrared
18.
Biophys Chem ; 269: 106510, 2021 02.
Article in English | MEDLINE | ID: covidwho-971712

ABSTRACT

The search for therapeutic drugs that can neutralize the effects of COVID-2019 (SARS-CoV-2) infection is the main focus of current research. The coronavirus main protease (Mpro) is an attractive target for anti-coronavirus drug design. Further, α-ketoamide is proved to be very effective as a reversible covalent-inhibitor against cysteine proteases. Herein, we report on the non-covalent to the covalent adduct formation mechanism of α-ketoamide-based inhibitor with the enzyme active site amino acids by QM/SQM model (QM = quantum mechanical, SQM = semi-empirical QM). To uncover the mechanism, we focused on two approaches: a concerted and a stepwise fashion. The concerted pathway proceeds via deprotonation of the thiol of cysteine (here, Cys145 SγH) and simultaneous reversible nucleophilic attack of sulfur onto the α-ketoamide warhead. In this work, we propose three plausible concerted pathways. On the contrary, in a traditional two-stage pathway, the first step is proton transfer from Cys145 SγH to His41 Nδ forming an ion pair, and consecutively, in the second step, the thiolate ion attacks the α-keto group to form a thiohemiketal. In this reaction, we find that the stability of the tetrahedral intermediate oxyanion/hydroxyl group plays an important role. Moreover, as the α-keto group has two faces Si or Re for the nucleophilic attack, we considered both possibilities of attack leading to S- and R-thiohemiketal. We computed the structural, electronic, and energetic parameters of all stationary points including transition states via ONIOM and pure DFT method. Additionally, to characterize covalent, weak noncovalent interaction (NCI) and hydrogen-bonds, we applied NCI-reduced density gradient (NCI-RDG) methods along with Bader's Quantum Theory of Atoms-in-Molecules (QTAIM) and natural bonding orbital (NBO) analysis.


Subject(s)
Amides/chemistry , Coronavirus/enzymology , Peptide Hydrolases/chemistry , Protease Inhibitors/chemistry , Viral Proteins/antagonists & inhibitors , Amides/metabolism , Binding Sites , Catalytic Domain , Coronavirus/isolation & purification , Coronavirus Infections/pathology , Coronavirus Infections/virology , Coronavirus M Proteins/antagonists & inhibitors , Coronavirus M Proteins/metabolism , Drug Design , Humans , Hydrogen Bonding , Molecular Docking Simulation , Peptide Hydrolases/metabolism , Protease Inhibitors/metabolism , Quantum Theory , Thermodynamics , Viral Proteins/metabolism
19.
Molecules ; 25(23)2020 Dec 03.
Article in English | MEDLINE | ID: covidwho-963646

ABSTRACT

The RNA-dependent RNA polymerase (RdRp) is an essential enzyme for the viral replication process, catalyzing the viral RNA synthesis using a metal ion-dependent mechanism. In recent years, RdRp has emerged as an optimal target for the development of antiviral drugs, as demonstrated by recent approvals of sofosbuvir and remdesivir against Hepatitis C virus (HCV) and severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), respectively. In this work, we overview the main sequence and structural features of the RdRp of emerging RNA viruses such as Coronaviruses, Flaviviruses, and HCV, as well as inhibition strategies implemented so far. While analyzing the structural information available on the RdRp of emerging RNA viruses, we provide examples of success stories such as for HCV and SARS-CoV-2. In contrast, Flaviviruses' story has raised attention about how the lack of structural details on catalytically-competent or ligand-bound RdRp strongly hampers the application of structure-based drug design, either in repurposing and conventional approaches.


Subject(s)
Antiviral Agents/chemistry , Antiviral Agents/pharmacology , RNA Viruses/enzymology , RNA-Dependent RNA Polymerase/chemistry , Amides/chemistry , Amides/pharmacology , Coronavirus/drug effects , Coronavirus/enzymology , Coronavirus/genetics , Drug Design , Enzyme Inhibitors/chemistry , Enzyme Inhibitors/pharmacology , Flavivirus/drug effects , Flavivirus/enzymology , Flavivirus/genetics , Hepacivirus/drug effects , Hepacivirus/enzymology , Hepacivirus/genetics , Humans , Pyrazines/chemistry , Pyrazines/pharmacology , RNA Virus Infections/epidemiology , RNA Viruses/drug effects , RNA-Dependent RNA Polymerase/antagonists & inhibitors , RNA-Dependent RNA Polymerase/metabolism , Small Molecule Libraries/chemistry , Small Molecule Libraries/pharmacology
20.
BMC Res Notes ; 13(1): 527, 2020 Nov 11.
Article in English | MEDLINE | ID: covidwho-917943

ABSTRACT

OBJECTIVES: The aim of this study was to use Ligand-based pharmacophore modelling approach for four established antiviral drugs, namely remdesivir, lopinavir, ritonavir and hydroxychloroquine for COVID-19 inhibitors as training sets. In this study Twenty vanillin derivatives together with monolaurin and tetrodotoxin were used as test sets to evaluate as potential SARS-CoV-2 inhibitors. The Structure-based pharmacophore modelling approach was also performed using 5RE6, 5REX and 5RFZ in order to analyse the binding site and ligand-protein complex interactions. RESULTS: The pharmacophore modelling mode of 5RE6 displayed two Hydrogen Bond Acceptors (HBA) and one Hydrophobic (HY) interaction. Besides, the pharmacophore model of 5REX showed two HBA and two HY interactions. Finally, the pharmacophore model of 5RFZ showed three HBA and one HY interaction. Based on ligand-based approach, 20 Schiff-based vanillin derivatives, showed strong MPro inhibition activity. This was due to their good alignment and common features to PDB-5RE6. Similarly, monolaurin and tetrodotoxin displayed some significant activity against SARS-CoV-2. From structure-based approach, vanillin derivatives (1) to (12) displayed some potent MPro inhibition against SARS-CoV-2. Favipiravir, chloroquine and hydroxychloroquine also showed some significant MPro inhibition.


Subject(s)
Antiviral Agents/pharmacology , Betacoronavirus/drug effects , Chloroquine/pharmacology , Cysteine Proteinase Inhibitors/pharmacology , Viral Nonstructural Proteins/antagonists & inhibitors , Amides/chemistry , Amides/pharmacology , Antiviral Agents/chemistry , Benzaldehydes/chemistry , Chloroquine/chemistry , Computer Simulation , Coronavirus 3C Proteases , Cysteine Endopeptidases , Cysteine Proteinase Inhibitors/chemistry , Humans , Hydroxychloroquine/chemistry , Hydroxychloroquine/pharmacology , Laurates/chemistry , Laurates/pharmacology , Microbial Sensitivity Tests , Models, Molecular , Monoglycerides/chemistry , Monoglycerides/pharmacology , Pyrazines/chemistry , Pyrazines/pharmacology , SARS-CoV-2 , Structure-Activity Relationship , Tetrodotoxin/chemistry , Tetrodotoxin/pharmacology
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