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1.
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
2.
Sci Rep ; 11(1): 19998, 2021 10 07.
Article in English | MEDLINE | ID: covidwho-1462031

ABSTRACT

Understanding the effects of metabolism on the rational design of novel and more effective drugs is still a considerable challenge. To the best of our knowledge, there are no entirely computational strategies that make it possible to predict these effects. From this perspective, the development of such methodologies could contribute to significantly reduce the side effects of medicines, leading to the emergence of more effective and safer drugs. Thereby, in this study, our strategy is based on simulating the electron ionization mass spectrometry (EI-MS) fragmentation of the drug molecules and combined with molecular docking and ADMET models in two different situations. In the first model, the drug is docked without considering the possible metabolic effects. In the second model, each of the intermediates from the EI-MS results is docked, and metabolism occurs before the drug accesses the biological target. As a proof of concept, in this work, we investigate the main antiviral drugs used in clinical research to treat COVID-19. As a result, our strategy made it possible to assess the biological activity and toxicity of all potential by-products. We believed that our findings provide new chemical insights that can benefit the rational development of novel drugs in the future.


Subject(s)
Antiviral Agents/metabolism , COVID-19/drug therapy , Drug Discovery , SARS-CoV-2/drug effects , Adenine/adverse effects , Adenine/analogs & derivatives , Adenine/metabolism , Adenine/pharmacology , Adenosine/adverse effects , Adenosine/analogs & derivatives , Adenosine/metabolism , Adenosine/pharmacology , Adenosine Monophosphate/adverse effects , Adenosine Monophosphate/analogs & derivatives , Adenosine Monophosphate/metabolism , Adenosine Monophosphate/pharmacology , Alanine/adverse effects , Alanine/analogs & derivatives , Alanine/metabolism , Alanine/pharmacology , Amides/adverse effects , Amides/metabolism , Amides/pharmacology , Antiviral Agents/adverse effects , Antiviral Agents/pharmacology , COVID-19/metabolism , Chloroquine/adverse effects , Chloroquine/analogs & derivatives , Chloroquine/metabolism , Chloroquine/pharmacology , Drug Design , Humans , Metabolic Networks and Pathways , Molecular Docking Simulation , Nitro Compounds/adverse effects , Nitro Compounds/metabolism , Nitro Compounds/pharmacology , Pyrazines/adverse effects , Pyrazines/metabolism , Pyrazines/pharmacology , Pyrrolidines/adverse effects , Pyrrolidines/metabolism , Pyrrolidines/pharmacology , Ribavirin/adverse effects , Ribavirin/metabolism , Ribavirin/pharmacology , SARS-CoV-2/metabolism , Thiazoles/adverse effects , Thiazoles/metabolism , Thiazoles/pharmacology
3.
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
4.
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
5.
Sci Rep ; 11(1): 7307, 2021 03 31.
Article in English | MEDLINE | ID: covidwho-1164913

ABSTRACT

Outcomes of various clinical studies for the coronavirus disease 2019 (COVID-19) treatment indicated that the drug acts via inhibition of multiple pathways (targets) is likely to be more successful and promising. Keeping this hypothesis intact, the present study describes for the first-time, Grazoprevir, an FDA approved anti-viral drug primarily approved for Hepatitis C Virus (HCV), mediated multiple pathway control via synergistic inhibition of viral entry targeting host cell Angiotensin-Converting Enzyme 2 (ACE-2)/transmembrane serine protease 2 (TMPRSS2) and viral replication targeting RNA-dependent RNA polymerase (RdRP). Molecular modeling followed by in-depth structural analysis clearly demonstrated that Grazoprevir interacts with the key residues of these targets. Futher, Molecular Dynamics (MD) simulations showed stability and burial of key residues after the complex formation. Finally, Molecular Mechanics Poisson-Boltzmann Surface Area (MM-PBSA) analysis identified the governing force of drug-receptor interactions and stability. Thus, we believe that Grazoprevir could be an effective therapeutics for the treatment of the COVID-19 pandemic with a promise of unlikely drug resistance owing to multiple inhibitions of eukaryotic and viral proteins, thus warrants further clinical studies.


Subject(s)
Amides/metabolism , Amides/pharmacology , Angiotensin-Converting Enzyme 2/metabolism , Antiviral Agents/pharmacology , Carbamates/metabolism , Carbamates/pharmacology , Coronavirus RNA-Dependent RNA Polymerase/metabolism , Cyclopropanes/metabolism , Cyclopropanes/pharmacology , Quinoxalines/metabolism , Quinoxalines/pharmacology , Sulfonamides/metabolism , Sulfonamides/pharmacology , Angiotensin-Converting Enzyme 2/chemistry , Antiviral Agents/metabolism , Coronavirus RNA-Dependent RNA Polymerase/chemistry , Drug Repositioning , Humans , Models, Molecular , Molecular Dynamics Simulation , Serine Endopeptidases/chemistry , Serine Endopeptidases/metabolism , Virus Internalization/drug effects
6.
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
7.
Eur J Med Chem ; 215: 113267, 2021 Apr 05.
Article in English | MEDLINE | ID: covidwho-1111592

ABSTRACT

Inhibitors of the proteasome have been extensively studied for their applications in the treatment of human diseases such as hematologic malignancies, autoimmune disorders, and viral infections. Many of the proteasome inhibitors reported in the literature target the non-primed site of proteasome's substrate binding pocket. In this study, we designed, synthesized and characterized a series of novel α-keto phenylamide derivatives aimed at both the primed and non-primed sites of the proteasome. In these derivatives, different substituted phenyl groups at the head group targeting the primed site were incorporated in order to investigate their structure-activity relationship and optimize the potency of α-keto phenylamides. In addition, the biological effects of modifications at the cap moiety, P1, P2 and P3 side chain positions were explored. Many derivatives displayed highly potent biological activities in proteasome inhibition and anticancer activity against a panel of six cancer cell lines, which were further rationalized by molecular modeling analyses. Furthermore, a representative α-ketoamide derivative was tested and found to be active in inhibiting the cellular infection of SARS-CoV-2 which causes the COVID-19 pandemic. These results demonstrate that this new class of α-ketoamide derivatives are potent anticancer agents and provide experimental evidence of the anti-SARS-CoV-2 effect by one of them, thus suggesting a possible new lead to develop antiviral therapeutics for COVID-19.


Subject(s)
Amides/pharmacology , Antineoplastic Agents/pharmacology , Antiviral Agents/pharmacology , Ketones/pharmacology , Proteasome Inhibitors/pharmacology , SARS-CoV-2/drug effects , Amides/chemical synthesis , Amides/metabolism , Antineoplastic Agents/chemical synthesis , Antineoplastic Agents/metabolism , Antiviral Agents/chemical synthesis , Antiviral Agents/metabolism , Binding Sites , Calpain/chemistry , Calpain/metabolism , Cell Line, Tumor , Coronavirus 3C Proteases/chemistry , Coronavirus 3C Proteases/metabolism , Drug Screening Assays, Antitumor , Humans , Ketones/chemical synthesis , Ketones/metabolism , Microbial Sensitivity Tests , Molecular Docking Simulation , Molecular Dynamics Simulation , Molecular Structure , Proteasome Endopeptidase Complex/chemistry , Proteasome Endopeptidase Complex/metabolism , Proteasome Inhibitors/chemical synthesis , Proteasome Inhibitors/metabolism , Protein Binding , Structure-Activity Relationship
8.
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
10.
J Phys Chem Lett ; 11(11): 4430-4435, 2020 Jun 04.
Article in English | MEDLINE | ID: covidwho-233085

ABSTRACT

The pandemic outbreak of a new coronavirus (CoV), SARS-CoV-2, has captured the world's attention, demonstrating that CoVs represent a continuous global threat. As this is a highly contagious virus, it is imperative to understand RNA-dependent-RNA-polymerase (RdRp), the key component in virus replication. Although the SARS-CoV-2 genome shares 80% sequence identity with severe acute respiratory syndrome SARS-CoV, their RdRps and nucleotidyl-transferases (NiRAN) share 98.1% and 93.2% identity, respectively. Sequence alignment of six coronaviruses demonstrated higher identity among their RdRps (60.9%-98.1%) and lower identity among their Spike proteins (27%-77%). Thus, a 3D structural model of RdRp, NiRAN, non-structural protein 7 (nsp7), and nsp8 of SARS-CoV-2 was generated by modeling starting from the SARS counterpart structures. Furthermore, we demonstrate the binding poses of three viral RdRp inhibitors (Galidesivir, Favipiravir, and Penciclovir), which were recently reported to have clinical significance for SARS-CoV-2. The network of interactions established by these drug molecules affirms their efficacy to inhibit viral RNA replication and provides an insight into their structure-based rational optimization for SARS-CoV-2 inhibition.


Subject(s)
Betacoronavirus/enzymology , Nucleotidyltransferases/chemistry , RNA-Dependent RNA Polymerase/chemistry , Adenine/analogs & derivatives , Adenine/chemistry , Adenine/metabolism , Adenosine/analogs & derivatives , Amides/chemistry , Amides/metabolism , Antiviral Agents/chemistry , Antiviral Agents/metabolism , Betacoronavirus/isolation & purification , Binding Sites , COVID-19 , Coronavirus Infections/epidemiology , Coronavirus Infections/pathology , Coronavirus Infections/virology , Humans , Molecular Docking Simulation , Nucleotidyltransferases/metabolism , Pandemics , Pneumonia, Viral/epidemiology , Pneumonia, Viral/pathology , Pneumonia, Viral/virology , Protein Structure, Tertiary , Pyrazines/chemistry , Pyrazines/metabolism , Pyrrolidines/chemistry , Pyrrolidines/metabolism , RNA-Dependent RNA Polymerase/metabolism , SARS-CoV-2
11.
Science ; 368(6489): 409-412, 2020 04 24.
Article in English | MEDLINE | ID: covidwho-164984

ABSTRACT

The coronavirus disease 2019 (COVID-19) pandemic caused by severe acute respiratory syndrome-coronavirus 2 (SARS-CoV-2) is a global health emergency. An attractive drug target among coronaviruses is the main protease (Mpro, also called 3CLpro) because of its essential role in processing the polyproteins that are translated from the viral RNA. We report the x-ray structures of the unliganded SARS-CoV-2 Mpro and its complex with an α-ketoamide inhibitor. This was derived from a previously designed inhibitor but with the P3-P2 amide bond incorporated into a pyridone ring to enhance the half-life of the compound in plasma. On the basis of the unliganded structure, we developed the lead compound into a potent inhibitor of the SARS-CoV-2 Mpro The pharmacokinetic characterization of the optimized inhibitor reveals a pronounced lung tropism and suitability for administration by the inhalative route.


Subject(s)
Amides/chemistry , Amides/pharmacology , Betacoronavirus/drug effects , Betacoronavirus/enzymology , Cysteine Endopeptidases/chemistry , Protease Inhibitors/chemistry , Protease Inhibitors/pharmacology , Viral Nonstructural Proteins/chemistry , Amides/metabolism , Animals , Antiviral Agents/chemistry , Antiviral Agents/metabolism , Antiviral Agents/pharmacokinetics , Antiviral Agents/pharmacology , Binding Sites , Cell Line, Tumor , Coronavirus 3C Proteases , Crystallography, X-Ray , Cysteine Endopeptidases/metabolism , Drug Design , Half-Life , Humans , Lung/metabolism , Mice , Models, Molecular , Protease Inhibitors/metabolism , Protease Inhibitors/pharmacokinetics , Protein Domains , Protein Multimerization , Pyridones/chemistry , SARS-CoV-2 , Viral Nonstructural Proteins/metabolism , Virus Replication/drug effects
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