Your browser doesn't support javascript.
Show: 20 | 50 | 100
Results 1 - 9 de 9
Filter
1.
Chem Commun (Camb) ; 57(83): 10911-10914, 2021 Oct 19.
Article in English | MEDLINE | ID: covidwho-1488037

ABSTRACT

We present Zn2+-dependent dimethyl-dipyridophenazine PNA conjugates as efficient RNA cleaving artificial enzymes. These PNAzymes display site-specific RNA cleavage with 10 minute half-lives and cleave clinically relevant RNA models.


Subject(s)
Peptide Nucleic Acids/chemistry , Phenazines/chemistry , Pyridines/chemistry , RNA/chemistry , Catalysis , Hydrogen-Ion Concentration , Hydrolysis , Ribonucleases/chemistry , Zinc/chemistry
2.
Molecules ; 26(19)2021 Sep 24.
Article in English | MEDLINE | ID: covidwho-1438673

ABSTRACT

We report the design and synthesis of a series of new 5-chloropyridinyl esters of salicylic acid, ibuprofen, indomethacin, and related aromatic carboxylic acids for evaluation against SARS-CoV-2 3CL protease enzyme. These ester derivatives were synthesized using EDC in the presence of DMAP to provide various esters in good to excellent yields. Compounds are stable and purified by silica gel chromatography and characterized using 1H-NMR, 13C-NMR, and mass spectral analysis. These synthetic derivatives were evaluated in our in vitro SARS-CoV-2 3CLpro inhibition assay using authentic SARS-CoV-2 3CLpro enzyme. Compounds were also evaluated in our in vitro antiviral assay using quantitative VeroE6 cell-based assay with RNAqPCR. A number of compounds exhibited potent SARS-CoV-2 3CLpro inhibitory activity and antiviral activity. Compound 9a was the most potent inhibitor, with an enzyme IC50 value of 160 nM. Compound 13b exhibited an enzyme IC50 value of 4.9 µM. However, it exhibited a potent antiviral EC50 value of 24 µM in VeroE6 cells. Remdesivir, an RdRp inhibitor, exhibited an antiviral EC50 value of 2.4 µM in the same assay. We assessed the mode of inhibition using mass spectral analysis which suggested the formation of a covalent bond with the enzyme. To obtain molecular insight, we have created a model of compound 9a bound to SARS-CoV-2 3CLpro in the active site.


Subject(s)
Anti-Inflammatory Agents, Non-Steroidal/chemistry , Anti-Inflammatory Agents, Non-Steroidal/pharmacology , COVID-19/drug therapy , Coronavirus 3C Proteases/antagonists & inhibitors , Protease Inhibitors/chemistry , Protease Inhibitors/pharmacology , SARS-CoV-2/drug effects , Animals , Antiviral Agents/chemistry , Antiviral Agents/pharmacology , Chlorocebus aethiops , Coronavirus 3C Proteases/metabolism , Esters/chemistry , Esters/pharmacology , Halogenation , Humans , Ibuprofen/analogs & derivatives , Ibuprofen/pharmacology , Indomethacin/analogs & derivatives , Indomethacin/pharmacology , Molecular Docking Simulation , Pyridines/chemistry , Pyridines/pharmacology , SARS-CoV-2/metabolism , Salicylic Acid/chemistry , Salicylic Acid/pharmacology , Vero Cells
3.
J Med Chem ; 64(19): 14702-14714, 2021 10 14.
Article in English | MEDLINE | ID: covidwho-1412442

ABSTRACT

Here, we report the synthesis, structure-activity relationship studies, enzyme inhibition, antiviral activity, and X-ray crystallographic studies of 5-chloropyridinyl indole carboxylate derivatives as a potent class of SARS-CoV-2 chymotrypsin-like protease inhibitors. Compound 1 exhibited a SARS-CoV-2 3CLpro inhibitory IC50 value of 250 nM and an antiviral EC50 value of 2.8 µM in VeroE6 cells. Remdesivir, an RNA-dependent RNA polymerase inhibitor, showed an antiviral EC50 value of 1.2 µM in the same assay. Compound 1 showed comparable antiviral activity with remdesivir in immunocytochemistry assays. Compound 7d with an N-allyl derivative showed the most potent enzyme inhibitory IC50 value of 73 nM. To obtain molecular insight into the binding properties of these molecules, X-ray crystal structures of compounds 2, 7b, and 9d-bound to SARS-CoV 3CLpro were determined, and their binding properties were compared.


Subject(s)
Coronavirus 3C Proteases/antagonists & inhibitors , Indoles/chemistry , Protease Inhibitors/chemistry , SARS-CoV-2/enzymology , Adenosine Monophosphate/analogs & derivatives , Adenosine Monophosphate/chemistry , Adenosine Monophosphate/metabolism , Alanine/analogs & derivatives , Alanine/chemistry , Alanine/metabolism , Animals , Binding Sites , COVID-19/pathology , COVID-19/virology , Chlorocebus aethiops , Coronavirus 3C Proteases/metabolism , Crystallography, X-Ray , Humans , Indoles/chemical synthesis , Indoles/metabolism , Molecular Dynamics Simulation , Protease Inhibitors/chemical synthesis , Protease Inhibitors/metabolism , Pyridines/chemistry , SARS-CoV-2/isolation & purification , Structure-Activity Relationship , Vero Cells
4.
J Mol Model ; 27(10): 276, 2021 Sep 04.
Article in English | MEDLINE | ID: covidwho-1391881

ABSTRACT

Rimegepant is a new medicine developed for the management of chronic headache due to migraine. This manuscript is an attempt to study the various structural, physical, and chemical properties of the molecules. The molecule was optimized using B3LYP functional with 6-311G + (2d,p) basis set. Excited state properties of the compound were studied using CAM-B3LYP functional with same basis sets using IEFPCM model in methanol for the implicit solvent atmosphere. The various electronic descriptors helped to identify the reactivity behavior and stability. The compound is found to possess good nonlinear optical properties in the gas phase. The various intramolecular electronic delocalizations and non-covalent interactions were analyzed and explained. As the compound contain several heterocyclic nitrogen atoms, they have potential proton abstraction features, which was analyzed energetically. The most important result from this study is from the molecular docking analysis which indicates that rimegepant binds irreversibly with three established SARS-CoV-2 proteins with ID 6LU7, 6M03, and 6W63 with docking scores - 9.2988, - 8.3629, and - 9.5421 kcal/mol respectively. Further assessment of docked complexes with molecular dynamics simulations revealed that hydrophobic interactions, water bridges, and π-π interactions play a significant role in stabilizing the ligand within the binding region of respective proteins. MMGBSA-free energies further demonstrated that rimegepant is more stable when complexed with 6LU7 among the selected PDB models. As the pharmacology and pharmacokinetics of this molecule are already established, rimegepant can be considered as an ideal candidate with potential for use in the treatment of COVID patients after clinical studies.


Subject(s)
Molecular Dynamics Simulation , Piperidines/chemistry , Protons , Pyridines/chemistry , SARS-CoV-2/chemistry , Viral Proteins/chemistry , SARS-CoV-2/metabolism , Viral Proteins/metabolism
5.
Molecules ; 26(12)2021 Jun 21.
Article in English | MEDLINE | ID: covidwho-1282543

ABSTRACT

Since December 2019, novel coronavirus disease 2019 (COVID-19) pandemic has caused tremendous economic loss and serious health problems worldwide. In this study, we investigated 14 natural compounds isolated from Amphimedon sp. via a molecular docking study, to examine their ability to act as anti-COVID-19 agents. Moreover, the pharmacokinetic properties of the most promising compounds were studied. The docking study showed that virtually screened compounds were effective against the new coronavirus via dual inhibition of SARS-CoV-2 RdRp and the 3CL main protease. In particular, nakinadine B (1), 20-hepacosenoic acid (11) and amphimedoside C (12) were the most promising compounds, as they demonstrated good interactions with the pockets of both enzymes. Based on the analysis of the molecular docking results, compounds 1 and 12 were selected for molecular dynamics simulation studies. Our results showed Amphimedon sp. to be a rich source for anti-COVID-19 metabolites.


Subject(s)
Biological Products/chemistry , Biological Products/pharmacology , Coronavirus 3C Proteases/chemistry , Porifera/chemistry , Porifera/metabolism , RNA-Dependent RNA Polymerase/chemistry , SARS-CoV-2/drug effects , Amino Sugars/chemistry , Amino Sugars/pharmacology , Animals , Antiviral Agents/chemistry , Antiviral Agents/pharmacology , Binding Sites , Biological Products/isolation & purification , Biological Products/pharmacokinetics , COVID-19/drug therapy , Computational Biology , Coronavirus 3C Proteases/antagonists & inhibitors , Coronavirus 3C Proteases/metabolism , Humans , Ligands , Models, Molecular , Molecular Docking Simulation , Molecular Dynamics Simulation , Protease Inhibitors/chemistry , Protease Inhibitors/pharmacology , Pyridines/chemistry , Pyridines/pharmacology , RNA-Dependent RNA Polymerase/antagonists & inhibitors , RNA-Dependent RNA Polymerase/metabolism , SARS-CoV-2/enzymology , SARS-CoV-2/metabolism
6.
Angew Chem Int Ed Engl ; 60(18): 10423-10429, 2021 04 26.
Article in English | MEDLINE | ID: covidwho-1114156

ABSTRACT

The main protease of SARS-CoV-2 (Mpro ), the causative agent of COVID-19, constitutes a significant drug target. A new fluorogenic substrate was kinetically compared to an internally quenched fluorescent peptide and shown to be ideally suitable for high throughput screening with recombinantly expressed Mpro . Two classes of protease inhibitors, azanitriles and pyridyl esters, were identified, optimized and subjected to in-depth biochemical characterization. Tailored peptides equipped with the unique azanitrile warhead exhibited concomitant inhibition of Mpro and cathepsin L, a protease relevant for viral cell entry. Pyridyl indole esters were analyzed by a positional scanning. Our focused approach towards Mpro inhibitors proved to be superior to virtual screening. With two irreversible inhibitors, azanitrile 8 (kinac /Ki =37 500 m-1 s-1 , Ki =24.0 nm) and pyridyl ester 17 (kinac /Ki =29 100 m-1 s-1 , Ki =10.0 nm), promising drug candidates for further development have been discovered.


Subject(s)
Antiviral Agents/pharmacology , COVID-19/drug therapy , Coronavirus 3C Proteases/antagonists & inhibitors , Nitriles/pharmacology , Protease Inhibitors/pharmacology , SARS-CoV-2/drug effects , Antiviral Agents/chemistry , COVID-19/metabolism , COVID-19/virology , Coronavirus 3C Proteases/metabolism , Drug Design , Drug Discovery , HEK293 Cells , High-Throughput Screening Assays , Humans , Molecular Docking Simulation , Nitriles/chemistry , Protease Inhibitors/chemistry , Pyridines/chemistry , Pyridines/pharmacology , SARS-CoV-2/enzymology , SARS-CoV-2/physiology , Virus Internalization/drug effects
7.
J Mol Model ; 26(12): 341, 2020 Nov 16.
Article in English | MEDLINE | ID: covidwho-926723

ABSTRACT

HER-2 type breast cancer is one of the most aggressive malignancies found in women. Tucatinib is recently developed and approved as a potential medicine to fight this disease. In this manuscript, we present the gross structural features of this compound and its reactivity and wave function properties using computational simulations. Density functional theory was used to optimise the ground state geometry of the molecule and molecular docking was used to predict biological activity. As the electrons interact with electromagnetic radiations, electronic excitations between different energy levels are analysed in detail using time-dependent density functional theory. Various intermolecular and intermolecular interactions are analysed and reaction sites for attacking electrophiles and nucleophiles identified. Information entropy calculations show that the compound is inherently stable. Docking with COVID-19 proteins show docking score of - 9.42, - 8.93, - 8.45 and - 8.32 kcal/mol respectively indicating high interaction between the drug and proteins. Hence, this is an ideal candidate to study repurposing of existing drugs to combat the pandemic.


Subject(s)
Antineoplastic Agents/chemistry , Antiviral Agents/chemistry , Betacoronavirus/chemistry , Electrons , Oxazoles/chemistry , Protease Inhibitors/chemistry , Pyridines/chemistry , Quinazolines/chemistry , Viral Nonstructural Proteins/antagonists & inhibitors , Antineoplastic Agents/metabolism , Antiviral Agents/metabolism , Betacoronavirus/enzymology , Binding Sites , Coronavirus 3C Proteases , Cysteine Endopeptidases/chemistry , Cysteine Endopeptidases/metabolism , Drug Repositioning , Humans , Hydrogen Bonding , Hydrophobic and Hydrophilic Interactions , Molecular Docking Simulation , Molecular Dynamics Simulation , Oxazoles/metabolism , Protease Inhibitors/metabolism , Protein Binding , Protein Interaction Domains and Motifs , Protein Structure, Secondary , Pyridines/metabolism , Quantum Theory , Quinazolines/metabolism , SARS-CoV-2 , Thermodynamics , Viral Nonstructural Proteins/chemistry , Viral Nonstructural Proteins/metabolism
8.
J Mol Graph Model ; 101: 107730, 2020 12.
Article in English | MEDLINE | ID: covidwho-863411

ABSTRACT

The SARS-CoV-2 main protease (Mpro) is an attractive target towards discovery of drugs to treat COVID-19 because of its key role in virus replication. The atomic structure of Mpro in complex with an α-ketoamide inhibitor (Lig13b) is available (PDB ID:6Y2G). Using 6Y2G and the prior knowledge that protease inhibitors could eradicate COVID-19, we designed a computational study aimed at identifying FDA-approved drugs that could interact with Mpro. We searched the DrugBank and PubChem for analogs and built a virtual library containing ∼33,000 conformers. Using high-throughput virtual screening and ligand docking, we identified Isavuconazonium, a ketoamide inhibitor (α-KI) and Pentagastrin as the top three molecules (Lig13b as the benchmark) based on docking energy. The ΔGbind of Lig13b, Isavuconazonium, α-KI, Pentagastrin was -28.1, -45.7, -44.7, -34.8 kcal/mol, respectively. Molecular dynamics simulation revealed that these ligands are stable within the Mpro active site. Binding of these ligands is driven by a variety of non-bonded interaction, including polar bonds, H-bonds, van der Waals and salt bridges. The overall conformational dynamics of the complexed-Mpro was slightly altered relative to apo-Mpro. This study demonstrates that three distinct classes molecules, Isavuconazonium (triazole), α-KI (ketoamide) and Pentagastrin (peptide) could serve as potential drugs to treat patients with COVID-19.


Subject(s)
Cysteine Endopeptidases/chemistry , Nitriles/pharmacology , Pentagastrin/pharmacology , Protease Inhibitors/pharmacology , Pyridines/pharmacology , Triazoles/pharmacology , Viral Nonstructural Proteins/antagonists & inhibitors , Viral Nonstructural Proteins/chemistry , Antiviral Agents/chemistry , Antiviral Agents/pharmacology , Catalytic Domain , Computer Simulation , Coronavirus 3C Proteases , Cysteine Endopeptidases/metabolism , Databases, Pharmaceutical , Drug Approval , Drug Discovery , Drug Repositioning , High-Throughput Screening Assays/methods , Ligands , Molecular Docking Simulation , Molecular Dynamics Simulation , Nitriles/chemistry , Pentagastrin/chemistry , Protease Inhibitors/chemistry , Pyridines/chemistry , Triazoles/chemistry , United States , United States Food and Drug Administration , Viral Nonstructural Proteins/metabolism
9.
J Infect Public Health ; 13(9): 1210-1223, 2020 Sep.
Article in English | MEDLINE | ID: covidwho-599724

ABSTRACT

BACKGROUND: The rapidly enlarging COVID-19 pandemic caused by the novel SARS-corona virus-2 is a global public health emergency of an unprecedented level. Unfortunately no treatment therapy or vaccine is yet available to counter the SARS-CoV-2 infection, which substantiates the need to expand research efforts in this direction. The indispensable function of the main protease in virus replication makes this enzyme a promising target for inhibitors screening and drug discovery to treat novel coronavirus infection. The recently concluded α-ketoamide ligand-bound X-ray crystal structure of SARS-CoV-2 Mpro (PDB ID: 6Y2F) from Zhang et al. has revealed the potential inhibitor binding mechanism and the molecular determinants responsible for substrate binding. METHODS: For the study, we have targeted the SARS-CoV-2 Mpro for the screening of FDA approved antiviral drugs and carried out molecular docking based virtual screening. Further molecular dynamic simulation studies of the top three selected drugs carried out to investigated for their binding affinity and stability in the SARS-CoV-2 Mpro active site. The phylogenetic analysis was also performed to know the relatedness between the SARS-CoV-2 genomes isolated from different countries. RESULTS: The phylogenetic analysis of the SARS-CoV-2 genome reveals that the virus is closely related to the Bat-SL-CoV and does not exhibit any divergence at the genomic level. Molecular docking studies revealed that among the 77 drugs, screened top ten drugs shows good binding affinities, whereas the top three drugs: Lopinavir-Ritonavir, Tipranavir, and Raltegravir were undergone for molecular dynamics simulation studies for their conformational stability in the active site of the SARS-CoV-2 Mpro protein. CONCLUSIONS: In the present study among the library of FDA approved antiviral drugs, the top three inhibitors Lopinavir-Ritonavir, Tipranavir, and Raltegravir show the best molecular interaction with the main protease of SARS-CoV-2. However, the in-vitro efficacy of the drug molecules screened in this study further needs to be corroborated by carrying out a biochemical and structural investigation.


Subject(s)
Antiviral Agents/chemistry , Betacoronavirus/enzymology , Coronavirus Infections/drug therapy , Cysteine Endopeptidases/chemistry , Drug Repositioning , Pneumonia, Viral/drug therapy , Protease Inhibitors/chemistry , Viral Nonstructural Proteins/chemistry , Betacoronavirus/genetics , COVID-19 , Coronavirus 3C Proteases , Drug Combinations , Humans , Lopinavir/chemistry , Molecular Conformation , Molecular Docking Simulation , Molecular Dynamics Simulation , Pandemics , Phylogeny , Pyridines/chemistry , Pyrones/chemistry , Raltegravir Potassium/chemistry , Ritonavir/chemistry , SARS-CoV-2 , Sulfonamides , Viral Nonstructural Proteins/antagonists & inhibitors
SELECTION OF CITATIONS
SEARCH DETAIL