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1.
Nat Commun ; 13(1): 1891, 2022 Apr 07.
Article in English | MEDLINE | ID: covidwho-1783979

ABSTRACT

The SARS-CoV-2 3CL protease is a critical drug target for small molecule COVID-19 therapy, given its likely druggability and essentiality in the viral maturation and replication cycle. Based on the conservation of 3CL protease substrate binding pockets across coronaviruses and using screening, we identified four structurally distinct lead compounds that inhibit SARS-CoV-2 3CL protease. After evaluation of their binding specificity, cellular antiviral potency, metabolic stability, and water solubility, we prioritized the GC376 scaffold as being optimal for optimization. We identified multiple drug-like compounds with <10 nM potency for inhibiting SARS-CoV-2 3CL and the ability to block SARS-CoV-2 replication in human cells, obtained co-crystal structures of the 3CL protease in complex with these compounds, and determined that they have pan-coronavirus activity. We selected one compound, termed coronastat, as an optimized lead and characterized it in pharmacokinetic and safety studies in vivo. Coronastat represents a new candidate for a small molecule protease inhibitor for the treatment of SARS-CoV-2 infection for eliminating pandemics involving coronaviruses.


Subject(s)
COVID-19 , Antiviral Agents/chemistry , Antiviral Agents/pharmacology , Antiviral Agents/therapeutic use , COVID-19/drug therapy , Cysteine Endopeptidases/chemistry , Humans , Molecular Docking Simulation , Pandemics , Peptide Hydrolases , Protease Inhibitors/chemistry , Protease Inhibitors/pharmacology , Protease Inhibitors/therapeutic use , SARS-CoV-2
2.
Molecules ; 27(6)2022 Mar 16.
Article in English | MEDLINE | ID: covidwho-1742559

ABSTRACT

The persistency of COVID-19 in the world and the continuous rise of its variants demand new treatments to complement vaccines. Computational chemistry can assist in the identification of moieties able to lead to new drugs to fight the disease. Fullerenes and carbon nanomaterials can interact with proteins and are considered promising antiviral agents. Here, we propose the possibility to repurpose fullerenes to clog the active site of the SARS-CoV-2 protease, Mpro. Through the use of docking, molecular dynamics, and energy decomposition techniques, it is shown that C60 has a substantial binding energy to the main protease of the SARS-CoV-2 virus, Mpro, higher than masitinib, a known inhibitor of the protein. Furthermore, we suggest the use of C70 as an innovative scaffold for the inhibition of SARS-CoV-2 Mpro. At odds with masitinib, both C60 and C70 interact more strongly with SARS-CoV-2 Mpro when different protonation states of the catalytic dyad are considered. The binding of fullerenes to Mpro is due to shape complementarity, i.e., vdW interactions, and is aspecific. As such, it is not sensitive to mutations that can eliminate or invert the charges of the amino acids composing the binding pocket. Fullerenic cages should therefore be more effective against the SARS-CoV-2 virus than the available inhibitors such as masinitib, where the electrostatic term plays a crucial role in the binding.


Subject(s)
COVID-19 , Fullerenes , COVID-19/drug therapy , Catalytic Domain , Cysteine Endopeptidases/chemistry , Drug Repositioning , Fullerenes/pharmacology , Humans , Peptide Hydrolases/metabolism , SARS-CoV-2 , Viral Proteins/metabolism
3.
Molecules ; 27(6)2022 Mar 09.
Article in English | MEDLINE | ID: covidwho-1732134

ABSTRACT

In the search for new anti-HIV-1 agents, two forms of phenylamino-phenoxy-quinoline derivatives have been synthesized, namely, 2-phenylamino-4-phenoxy-quinoline and 6-phenylamino-4-phenoxy-quinoline. In this study, the binding interactions of phenylamino-phenoxy-quinoline derivatives and six commercially available drugs (hydroxychloroquine, ritonavir, remdesivir, S-217622, N3, and PF-07321332) with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) main protease (Mpro) were investigated using molecular docking and the ONIOM method. The molecular docking showed the hydrogen bonding and hydrophobic interactions of all the compounds in the pocket of SARS-CoV-2 main protease (Mpro), which plays an important role for the division and proliferation of the virus into the cell. The binding free energy values between the ligands and Mpro ranged from -7.06 to -10.61 kcal/mol. The molecular docking and ONIOM results suggested that 4-(2',6'-dimethyl-4'-cyanophenoxy)-2-(4″-cyanophenyl)-aminoquinoline and 4-(4'-cyanophenoxy)-2-(4″-cyanophenyl)-aminoquinoline have low binding energy values and appropriate molecular properties; moreover, both compounds could bind to Mpro via hydrogen bonding and Pi-Pi stacking interactions with amino acid residues, namely, HIS41, GLU166, and GLN192. These amino acids are related to the proteolytic cleavage process of the catalytic triad mechanisms. Therefore, this study provides important information for further studies on synthetic quinoline derivatives as antiviral candidates in the treatment of SARS-CoV-2.


Subject(s)
COVID-19 , Quinolines , COVID-19/drug therapy , Cysteine Endopeptidases/chemistry , Humans , Lactams , Leucine , Molecular Docking Simulation , Nitriles , Peptide Hydrolases , Proline , Quinolines/pharmacology , SARS-CoV-2 , Viral Proteins/metabolism
4.
Molecules ; 25(19)2020 Oct 06.
Article in English | MEDLINE | ID: covidwho-1389458

ABSTRACT

A novel series of some hydrazones bearing thiazole moiety were generated via solvent-drop grinding of thiazole carbohydrazide 2 with various carbonyl compounds. Also, dehydrative-cyclocondensation of 2 with active methylene compounds or anhydrides gave the respective pyarzole or pyrazine derivatives. The structures of the newly synthesized compounds were established based on spectroscopic evidences and their alternative syntheses. Additionally, the anti-viral activity of all the products was tested against SARS-CoV-2 main protease (Mpro) using molecular docking combined with molecular dynamics simulation (MDS). The average binding affinities of the compounds 3a, 3b, and 3c (-8.1 ± 0.33 kcal/mol, -8.0 ± 0.35 kcal/mol, and -8.2 ± 0.21 kcal/mol, respectively) are better than that of the positive control Nelfinavir (-6.9 ± 0.51 kcal/mol). This shows the possibility of these three compounds to effectively bind to SARS-CoV-2 Mpro and hence, contradict the virus lifecycle.


Subject(s)
Antiviral Agents/chemical synthesis , Betacoronavirus/enzymology , Hydrazones/chemical synthesis , Protease Inhibitors/chemical synthesis , Pyrazines/chemical synthesis , Pyrazoles/chemical synthesis , Viral Nonstructural Proteins/antagonists & inhibitors , Antiviral Agents/pharmacology , Betacoronavirus/chemistry , Betacoronavirus/drug effects , Binding Sites , COVID-19 , Coronavirus 3C Proteases , Coronavirus Infections/drug therapy , Cysteine Endopeptidases/chemistry , Cysteine Endopeptidases/metabolism , Drug Discovery , Humans , Hydrazones/pharmacology , Molecular Docking Simulation , Molecular Dynamics Simulation , Pandemics , Pneumonia, Viral/drug therapy , Protease Inhibitors/pharmacology , Protein Binding , Protein Conformation, alpha-Helical , Protein Conformation, beta-Strand , Protein Interaction Domains and Motifs , Pyrazines/pharmacology , Pyrazoles/pharmacology , SARS-CoV-2 , Thermodynamics , User-Computer Interface , Viral Nonstructural Proteins/chemistry , Viral Nonstructural Proteins/metabolism
5.
Sci Adv ; 6(28): eabb8097, 2020 07.
Article in English | MEDLINE | ID: covidwho-1388430

ABSTRACT

The prevalence of respiratory illness caused by the novel SARS-CoV-2 virus associated with multiple organ failures is spreading rapidly because of its contagious human-to-human transmission and inadequate globalhealth care systems. Pharmaceutical repurposing, an effective drug development technique using existing drugs, could shorten development time and reduce costs compared to those of de novo drug discovery. We carried out virtual screening of antiviral compounds targeting the spike glycoprotein (S), main protease (Mpro), and the SARS-CoV-2 receptor binding domain (RBD)-angiotensin-converting enzyme 2 (ACE2) complex of SARS-CoV-2. PC786, an antiviral polymerase inhibitor, showed enhanced binding affinity to all the targets. Furthermore, the postfusion conformation of the trimeric S protein RBD with ACE2 revealed conformational changes associated with PC786 drug binding. Exploiting immunoinformatics to identify T cell and B cell epitopes could guide future experimental studies with a higher probability of discovering appropriate vaccine candidates with fewer experiments and higher reliability.


Subject(s)
Antiviral Agents/pharmacology , Betacoronavirus/immunology , Coronavirus Infections/prevention & control , Cysteine Endopeptidases/chemistry , Drug Design , Pandemics/prevention & control , Peptidyl-Dipeptidase A/chemistry , Pneumonia, Viral/prevention & control , Spike Glycoprotein, Coronavirus/chemistry , Viral Nonstructural Proteins/chemistry , Angiotensin-Converting Enzyme 2 , Benzamides , Benzazepines , Betacoronavirus/drug effects , Betacoronavirus/metabolism , Binding Sites , COVID-19 , Coronavirus 3C Proteases , Coronavirus Infections/immunology , Coronavirus Infections/virology , Cysteine Endopeptidases/immunology , Cysteine Endopeptidases/metabolism , Drug Evaluation, Preclinical , Epitopes, B-Lymphocyte/drug effects , Epitopes, B-Lymphocyte/immunology , Epitopes, T-Lymphocyte/drug effects , Epitopes, T-Lymphocyte/immunology , Humans , Molecular Docking Simulation , Peptidyl-Dipeptidase A/immunology , Peptidyl-Dipeptidase A/metabolism , Pneumonia, Viral/immunology , Pneumonia, Viral/virology , Protein Binding , Protein Conformation , Protein Domains , Protein Interaction Domains and Motifs , SARS-CoV-2 , Spike Glycoprotein, Coronavirus/immunology , Spike Glycoprotein, Coronavirus/metabolism , Spiro Compounds/pharmacology , Viral Nonstructural Proteins/immunology , Viral Nonstructural Proteins/metabolism
6.
SAR QSAR Environ Res ; 31(7): 511-526, 2020 Jul.
Article in English | MEDLINE | ID: covidwho-1301250

ABSTRACT

In the context of recently emerged pandemic of COVID-19, we have performed two-dimensional quantitative structure-activity relationship (2D-QSAR) modelling using SARS-CoV-3CLpro enzyme inhibitors for the development of a multiple linear regression (MLR) based model. We have used 2D descriptors with an aim to develop an easily interpretable, transferable and reproducible model which may be used for quick prediction of SAR-CoV-3CLpro inhibitory activity for query compounds in the screening process. Based on the insights obtained from the developed 2D-QSAR model, we have identified the structural features responsible for the enhancement of the inhibitory activity against 3CLpro enzyme. Moreover, we have performed the molecular docking analysis using the most and least active molecules from the dataset to understand the molecular interactions involved in binding, and the results were then correlated with the essential structural features obtained from the 2D-QSAR model. Additionally, we have performed in silico predictions of SARS-CoV 3CLpro enzyme inhibitory activity of a total of 50,437 compounds obtained from two anti-viral drug databases (CAS COVID-19 antiviral candidate compound database and another recently reported list of prioritized compounds from the ZINC15 database) using the developed model and provided prioritized compounds for experimental detection of their performance for SARS-CoV 3CLpro enzyme inhibition.


Subject(s)
Betacoronavirus/enzymology , Cysteine Endopeptidases/chemistry , Protease Inhibitors/chemistry , Protease Inhibitors/pharmacology , Quantitative Structure-Activity Relationship , Antiviral Agents/chemistry , Antiviral Agents/pharmacology , Betacoronavirus/drug effects , COVID-19 , Coronavirus Infections , Drug Design , Linear Models , Molecular Docking Simulation , Pandemics , Pneumonia, Viral , SARS-CoV-2
7.
Viruses ; 12(9)2020 08 26.
Article in English | MEDLINE | ID: covidwho-1121700

ABSTRACT

Coronaviruses are viral infections that have a significant ability to impact human health. Coronaviruses have produced two pandemics and one epidemic in the last two decades. The current pandemic has created a worldwide catastrophe threatening the lives of over 15 million as of July 2020. Current research efforts have been focused on producing a vaccine or repurposing current drug compounds to develop a therapeutic. There is, however, a need to study the active site preferences of relevant targets, such as the SARS-CoV-2 main protease (SARS-CoV-2 Mpro), to determine ways to optimize these drug compounds. The ensemble docking and characterization work described in this article demonstrates the multifaceted features of the SARS-CoV-2 Mpro active site, molecular guidelines to improving binding affinity, and ultimately the optimization of drug candidates. A total of 220 compounds were docked into both the 5R7Z and 6LU7 SARS-CoV-2 Mpro crystal structures. Several key preferences for strong binding to the four subsites (S1, S1', S2, and S4) were identified, such as accessing hydrogen binding hotspots, hydrophobic patches, and utilization of primarily aliphatic instead of aromatic substituents. After optimization efforts using the design guidelines developed from the molecular docking studies, the average docking score of the parent compounds was improved by 6.59 -log10(Kd) in binding affinity which represents an increase of greater than six orders of magnitude. Using the optimization guidelines, the SARS-CoV-2 Mpro inhibitor cinanserin was optimized resulting in an increase in binding affinity of 4.59 -log10(Kd) and increased protease inhibitor bioactivity. The results of molecular dynamic (MD) simulation of cinanserin-optimized compounds CM02, CM06, and CM07 revealed that CM02 and CM06 fit well into the active site of SARS-CoV-2 Mpro [Protein Data Bank (PDB) accession number 6LU7] and formed strong and stable interactions with the key residues, Ser-144, His-163, and Glu-166. The enhanced binding affinity produced demonstrates the utility of the design guidelines described. The work described herein will assist scientists in developing potent COVID-19 antivirals.


Subject(s)
Antiviral Agents/pharmacology , Betacoronavirus/drug effects , Coronavirus Infections/drug therapy , Coronavirus Infections/virology , Cysteine Endopeptidases/metabolism , Pneumonia, Viral/drug therapy , Pneumonia, Viral/virology , Protease Inhibitors/pharmacology , Viral Nonstructural Proteins/metabolism , Antiviral Agents/chemistry , Betacoronavirus/enzymology , Binding Sites , COVID-19 , Catalytic Domain , Coronavirus 3C Proteases , Cysteine Endopeptidases/chemistry , Drug Design , Drug Repositioning , Humans , Molecular Docking Simulation/methods , Molecular Dynamics Simulation , Pandemics , Protease Inhibitors/chemistry , Protein Conformation , SARS-CoV-2 , Viral Nonstructural Proteins/chemistry
8.
Biochem Biophys Res Commun ; 533(3): 467-473, 2020 Dec 10.
Article in English | MEDLINE | ID: covidwho-1064868

ABSTRACT

The coronavirus disease 2019 (COVID-19) pandemic caused by 2019 novel coronavirus (2019-nCoV) has been a crisis of global health, whereas the effective vaccines against 2019-nCoV are still under development. Alternatively, utilization of old drugs or available medicine that can suppress the viral activity or replication may provide an urgent solution to suppress the rapid spread of 2019-nCoV. Andrographolide is a highly abundant natural product of the medicinal plant, Andrographis paniculata, which has been clinically used for inflammatory diseases and anti-viral therapy. We herein demonstrate that both andrographolide and its fluorescent derivative, the nitrobenzoxadiazole-conjugated andrographolide (Andro- NBD), suppressed the main protease (Mpro) activities of 2019-nCoV and severe acute respiratory syndrome coronavirus (SARS-CoV). Moreover, Andro-NBD was shown to covalently link its fluorescence to these proteases. Further mass spectrometry (MS) analysis suggests that andrographolide formed a covalent bond with the active site Cys145 of either 2019-nCoV Mpro or SARS-CoV Mpro. Consistently, molecular modeling analysis supported the docking of andrographolide within the catalytic pockets of both viral Mpros. Considering that andrographolide is used in clinical practice with acceptable safety and its diverse pharmacological activities that could be beneficial for attenuating COVID-19 symptoms, extensive investigation of andrographolide on the suppression of 2019-nCoV as well as its application in COVID-19 therapy is suggested.


Subject(s)
Cysteine Endopeptidases/metabolism , Diterpenes/pharmacology , Protease Inhibitors/chemistry , Protease Inhibitors/pharmacology , Viral Nonstructural Proteins/antagonists & inhibitors , Viral Nonstructural Proteins/metabolism , Betacoronavirus/enzymology , Catalytic Domain , Coronavirus 3C Proteases , Cysteine Endopeptidases/chemistry , Diterpenes/chemistry , Fluorescent Dyes/chemistry , Fluorescent Dyes/pharmacology , Molecular Docking Simulation , Protein Conformation , Protein Multimerization , SARS Virus/enzymology , SARS-CoV-2 , Viral Nonstructural Proteins/chemistry
9.
Virus Res ; 288: 198102, 2020 10 15.
Article in English | MEDLINE | ID: covidwho-1003124

ABSTRACT

Coronavirus disease 2019 (COVID-19) is an infectious disease, caused by a newly emerged highly pathogenic virus called novel severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Targeting the main protease (Mpro, 3CLpro) of SARS-CoV-2 is an appealing approach for drug development because this enzyme plays a significant role in the viral replication and transcription. The available crystal structures of SARS-CoV-2 Mpro determined in the presence of different ligands and inhibitor-like compounds provide a platform for the quick development of selective inhibitors of SARS-CoV-2 Mpro. In this study, we utilized the structural information of co-crystallized SARS-CoV-2 Mpro for the structure-guided drug discovery of high-affinity inhibitors from the PubChem database. The screened compounds were selected on the basis of their physicochemical properties, drug-likeliness, and strength of affinity to the SARS-CoV-2 Mpro. Finally, we have identified 6-Deaminosinefungin (PubChem ID: 10428963) and UNII-O9H5KY11SV (PubChem ID: 71481120) as potential inhibitors of SARS-CoV-2 Mpro which may be further exploited in drug development to address SARS-CoV-2 pathogenesis. Both compounds are structural analogs of known antivirals, having considerable protease inhibitory potential with improved pharmacological properties. All-atom molecular dynamics simulations suggested SARS-CoV-2 Mpro in complex with these compounds is stable during the simulation period with minimal structural changes. This work provides enough evidence for further implementation of the identified compounds in the development of effective therapeutics of COVID-19.


Subject(s)
Aminoglycosides/chemistry , Antiviral Agents/chemistry , Betacoronavirus/chemistry , Protease Inhibitors/chemistry , Pyrrolidines/chemistry , Viral Nonstructural Proteins/antagonists & inhibitors , Aminoglycosides/metabolism , Antiviral Agents/metabolism , Betacoronavirus/enzymology , COVID-19 , Catalytic Domain , Coronavirus 3C Proteases , Coronavirus Infections/drug therapy , Cysteine Endopeptidases/chemistry , Cysteine Endopeptidases/genetics , Cysteine Endopeptidases/metabolism , Drug Discovery , Gene Expression , Humans , Molecular Docking Simulation , Molecular Dynamics Simulation , Pandemics , Pneumonia, Viral/drug therapy , Protease Inhibitors/metabolism , Protein Binding , Protein Conformation, alpha-Helical , Protein Conformation, beta-Strand , Protein Interaction Domains and Motifs , Pyrrolidines/metabolism , SARS-CoV-2 , Substrate Specificity , Sulfonic Acids , Thermodynamics , User-Computer Interface , Viral Nonstructural Proteins/chemistry , Viral Nonstructural Proteins/genetics , Viral Nonstructural Proteins/metabolism
10.
Nat Commun ; 11(1): 3202, 2020 06 24.
Article in English | MEDLINE | ID: covidwho-981316

ABSTRACT

The COVID-19 disease caused by the SARS-CoV-2 coronavirus has become a pandemic health crisis. An attractive target for antiviral inhibitors is the main protease 3CL Mpro due to its essential role in processing the polyproteins translated from viral RNA. Here we report the room temperature X-ray structure of unliganded SARS-CoV-2 3CL Mpro, revealing the ligand-free structure of the active site and the conformation of the catalytic site cavity at near-physiological temperature. Comparison with previously reported low-temperature ligand-free and inhibitor-bound structures suggest that the room temperature structure may provide more relevant information at physiological temperatures for aiding in molecular docking studies.


Subject(s)
Betacoronavirus/enzymology , Cysteine Endopeptidases/chemistry , Viral Nonstructural Proteins/chemistry , Catalytic Domain , Coronavirus 3C Proteases , Crystallography, X-Ray , Cysteine Endopeptidases/metabolism , Cysteine Proteinase Inhibitors/metabolism , Ligands , Models, Molecular , Molecular Dynamics Simulation , Protein Binding , Protein Conformation , Protein Domains , Protein Structure, Secondary , SARS-CoV-2 , Temperature , Viral Nonstructural Proteins/antagonists & inhibitors , Viral Nonstructural Proteins/metabolism
11.
J Proteome Res ; 19(11): 4706-4717, 2020 11 06.
Article in English | MEDLINE | ID: covidwho-950742

ABSTRACT

Corona virus disease (COVID-19) is a dangerous disease rapidly spreading all over the world today. Currently there are no treatment options for it. Drug repurposing studies explored the potency of antimalarial drugs, chloroquine and hydroxychloroquine, against SARS-CoV-2 virus. These drugs can inhibit the viral protease, called chymotrypsin-like cysteine protease, also known as Main protease (3CLpro); hence, we studied the binding efficiencies of 4-aminoquinoline and 8-aminoquinoline analogs of chloroquine. Six compounds furnished better binding energies than chloroquine and hydroxychloroquine. The interactions with the active site residues especially with Cys145 and His41, which are involved in catalytic diad for proteolysis, make these compounds potent main protease inhibitors. A regression model correlating binding energy and the molecular descriptors for chloroquine analogs was generated with R2 = 0.9039 and Q2 = 0.8848. This model was used to screen new analogs of primaquine and molecules from the Asinex compound library. The docking and regression analysis showed these analogs to be more potent inhibitors of 3CLpro than hydroxychloroquine and primaquine. The molecular dynamic simulations of the hits were carried out to determine the binding stabilities. Finally, we propose four compounds that show drug likeness toward SARS-CoV-2 that can be further validated through in vitro and in vivo studies.


Subject(s)
Betacoronavirus , Chloroquine , Coronavirus Infections/virology , Cysteine Endopeptidases , Pneumonia, Viral/virology , Protease Inhibitors , Viral Nonstructural Proteins , Betacoronavirus/chemistry , Betacoronavirus/metabolism , COVID-19 , Catalytic Domain , Chloroquine/analogs & derivatives , Chloroquine/chemistry , Chloroquine/metabolism , Coronavirus 3C Proteases , Cysteine Endopeptidases/chemistry , Cysteine Endopeptidases/metabolism , Humans , Hydroxychloroquine/chemistry , Hydroxychloroquine/metabolism , Molecular Docking Simulation , Molecular Dynamics Simulation , Pandemics , Protease Inhibitors/chemistry , Protease Inhibitors/metabolism , Protein Binding , SARS-CoV-2 , Viral Nonstructural Proteins/chemistry , Viral Nonstructural Proteins/metabolism
12.
Nat Commun ; 11(1): 5877, 2020 11 18.
Article in English | MEDLINE | ID: covidwho-933685

ABSTRACT

Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2), the pathogen that causes the disease COVID-19, produces replicase polyproteins 1a and 1ab that contain, respectively, 11 or 16 nonstructural proteins (nsp). Nsp5 is the main protease (Mpro) responsible for cleavage at eleven positions along these polyproteins, including at its own N- and C-terminal boundaries, representing essential processing events for subsequent viral assembly and maturation. We have determined X-ray crystallographic structures of this cysteine protease in its wild-type free active site state at 1.8 Å resolution, in its acyl-enzyme intermediate state with the native C-terminal autocleavage sequence at 1.95 Å resolution and in its product bound state at 2.0 Å resolution by employing an active site mutation (C145A). We characterize the stereochemical features of the acyl-enzyme intermediate including critical hydrogen bonding distances underlying catalysis in the Cys/His dyad and oxyanion hole. We also identify a highly ordered water molecule in a position compatible for a role as the deacylating nucleophile in the catalytic mechanism and characterize the binding groove conformational changes and dimerization interface that occur upon formation of the acyl-enzyme. Collectively, these crystallographic snapshots provide valuable mechanistic and structural insights for future antiviral therapeutic development including revised molecular docking strategies based on Mpro inhibition.


Subject(s)
Betacoronavirus/enzymology , Cysteine Endopeptidases/chemistry , Viral Nonstructural Proteins/chemistry , Betacoronavirus/chemistry , Binding Sites , Catalytic Domain , Coronavirus 3C Proteases , Crystallography, X-Ray , Cysteine Endopeptidases/genetics , Cysteine Endopeptidases/metabolism , Dimerization , Humans , Models, Molecular , Mutation , Protease Inhibitors/metabolism , Protein Conformation , SARS-CoV-2 , Substrate Specificity , Viral Nonstructural Proteins/antagonists & inhibitors , Viral Nonstructural Proteins/genetics , Viral Nonstructural Proteins/metabolism
13.
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
14.
Sci Rep ; 10(1): 19125, 2020 11 05.
Article in English | MEDLINE | ID: covidwho-912908

ABSTRACT

The current outbreak of Covid-19 infection due to SARS-CoV-2, a virus from the coronavirus family, has become a major threat to human healthcare. The virus has already infected more than 44 M people and the number of deaths reported has reached more than 1.1 M which may be attributed to lack of medicine. The traditional drug discovery approach involves many years of rigorous research and development and demands for a huge investment which cannot be adopted for the ongoing pandemic infection. Rather we need a swift and cost-effective approach to inhibit and control the viral infection. With the help of computational screening approaches and by choosing appropriate chemical space, it is possible to identify lead drug-like compounds for Covid-19. In this study, we have used the Drugbank database to screen compounds against the most important viral targets namely 3C-like protease (3CLpro), papain-like protease (PLpro), RNA-dependent RNA polymerase (RdRp) and the spike (S) protein. These targets play a major role in the replication/transcription and host cell recognition, therefore, are vital for the viral reproduction and spread of infection. As the structure based computational screening approaches are more reliable, we used the crystal structures for 3C-like main protease and spike protein. For the remaining targets, we used the structures based on homology modeling. Further, we employed two scoring methods based on binding free energies implemented in AutoDock Vina and molecular mechanics-generalized Born surface area approach. Based on these results, we propose drug cocktails active against the three viral targets namely 3CLpro, PLpro and RdRp. Interestingly, one of the identified compounds in this study i.e. Baloxavir marboxil has been under clinical trial for the treatment of Covid-19 infection. In addition, we have identified a few compounds such as Phthalocyanine, Tadalafil, Lonafarnib, Nilotinib, Dihydroergotamine, R-428 which can bind to all three targets simultaneously and can serve as multi-targeting drugs. Our study also included calculation of binding energies for various compounds currently under drug trials. Among these compounds, it is found that Remdesivir binds to targets, 3CLpro and RdRp with high binding affinity. Moreover, Baricitinib and Umifenovir were found to have superior target-specific binding while Darunavir is found to be a potential multi-targeting drug. As far as we know this is the first study where the compounds from the Drugbank database are screened against four vital targets of SARS-CoV-2 and illustrates that the computational screening using a double scoring approach can yield potential drug-like compounds against Covid-19 infection.


Subject(s)
Coronavirus Infections/drug therapy , Databases, Pharmaceutical , Drug Evaluation, Preclinical/methods , Molecular Targeted Therapy , Pneumonia, Viral/drug therapy , COVID-19 , Coronavirus 3C Proteases , Cost-Benefit Analysis , Cysteine Endopeptidases/chemistry , Cysteine Endopeptidases/metabolism , Drug Evaluation, Preclinical/economics , Humans , Molecular Docking Simulation , Pandemics , Protein Conformation , Viral Nonstructural Proteins/antagonists & inhibitors , Viral Nonstructural Proteins/chemistry , Viral Nonstructural Proteins/metabolism
15.
Phys Chem Chem Phys ; 22(43): 25335-25343, 2020 Nov 21.
Article in English | MEDLINE | ID: covidwho-899989

ABSTRACT

Coronavirus disease 2019 (COVID-19) is an ongoing global pandemic with very limited specific treatments. To fight COVID-19, various traditional antiviral medicines have been prescribed in China to infected patients with mild to moderate symptoms and received unexpected success in controlling the disease. However, the molecular mechanisms of how these herbal medicines interact with the SARS-CoV-2 virus that causes COVID-19 have remained elusive. It is well known that the main protease (Mpro) of SARS-CoV-2 plays an important role in maturation of many viral proteins such as the RNA-dependent RNA polymerase. Here, we explore the underlying molecular mechanisms of the computationally determined top candidate, namely, rutin which is a key component in many traditional antiviral medicines such as Lianhuaqinwen and Shuanghuanlian, for inhibiting the viral target-Mpro. Using in silico methods (docking and molecular dynamics simulations), we revealed the dynamics and energetics of rutin when interacting with the Mpro of SARS-CoV-2, suggesting that the highly hydrophilic rutin molecule can be bound inside the Mpro's pocket (active site) and possibly inhibit its biological functions. In addition, we optimized the structure of rutin and designed two more hydrophobic analogs, M1 and M2, which satisfy the rule of five for western medicines and demonstrated that they (M2 in particular) possess much stronger binding affinities to the SARS-COV-2s Mpro than rutin, due to the enhanced hydrophobic interaction as well as more hydrogen bonds. Therefore, our results provide invaluable insights into the mechanism of a ligand's binding inside the Mpro and shed light on future structure-based designs of high-potent inhibitors for SARS-CoV-2 Mpro.


Subject(s)
Betacoronavirus/enzymology , Cysteine Endopeptidases/metabolism , Protease Inhibitors/chemistry , Rutin/chemistry , Viral Nonstructural Proteins/metabolism , Betacoronavirus/isolation & purification , Binding Sites , COVID-19 , Coronavirus 3C Proteases , Coronavirus Infections/pathology , Coronavirus Infections/virology , Cysteine Endopeptidases/chemistry , Herbal Medicine , Humans , Hydrogen Bonding , Molecular Docking Simulation , Molecular Dynamics Simulation , Pandemics , Pneumonia, Viral/pathology , Pneumonia, Viral/virology , Protease Inhibitors/metabolism , Protein Domains , Rutin/metabolism , SARS-CoV-2 , Thermodynamics , Viral Nonstructural Proteins/chemistry
16.
J Chem Inf Model ; 60(10): 5080-5102, 2020 10 26.
Article in English | MEDLINE | ID: covidwho-889114

ABSTRACT

A new coronavirus (SARS-CoV-2) is a global threat to world health and economy. Its dimeric main protease (Mpro), which is required for the proteolytic cleavage of viral precursor proteins, is a good candidate for drug development owing to its conservation and the absence of a human homolog. Improving our understanding of Mpro behavior can accelerate the discovery of effective therapies to reduce mortality. All-atom molecular dynamics (MD) simulations (100 ns) of 50 mutant Mpro dimers obtained from filtered sequences from the GISAID database were analyzed using root-mean-square deviation, root-mean-square fluctuation, Rg, averaged betweenness centrality, and geometry calculations. The results showed that SARS-CoV-2 Mpro essentially behaves in a similar manner to its SAR-CoV homolog. However, we report the following new findings from the variants: (1) Residues GLY15, VAL157, and PRO184 have mutated more than once in SARS CoV-2; (2) the D48E variant has lead to a novel "TSEEMLN"" loop at the binding pocket; (3) inactive apo Mpro does not show signs of dissociation in 100 ns MD; (4) a non-canonical pose for PHE140 widens the substrate binding surface; (5) dual allosteric pockets coinciding with various stabilizing and functional components of the substrate binding pocket were found to display correlated compaction dynamics; (6) high betweenness centrality values for residues 17 and 128 in all Mpro samples suggest their high importance in dimer stability-one such consequence has been observed for the M17I mutation whereby one of the N-fingers was highly unstable. (7) Independent coarse-grained Monte Carlo simulations suggest a relationship between the rigidity/mutability and enzymatic function. Our entire approach combining database preparation, variant retrieval, homology modeling, dynamic residue network (DRN), relevant conformation retrieval from 1-D kernel density estimates from reaction coordinates to other existing approaches of structural analysis, and data visualization within the coronaviral Mpro is also novel and is applicable to other coronaviral proteins.


Subject(s)
Betacoronavirus/genetics , Coronavirus Infections/virology , Cysteine Endopeptidases/genetics , Pneumonia, Viral/virology , Point Mutation , Viral Nonstructural Proteins/genetics , Betacoronavirus/chemistry , Binding Sites , COVID-19 , Coronavirus 3C Proteases , Coronavirus Infections/epidemiology , Cysteine Endopeptidases/chemistry , Humans , Molecular Dynamics Simulation , Mutation , Pandemics , Pneumonia, Viral/epidemiology , Protein Conformation , Protein Multimerization , SARS-CoV-2 , Viral Nonstructural Proteins/chemistry
17.
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
18.
Nat Commun ; 11(1): 5047, 2020 10 07.
Article in English | MEDLINE | ID: covidwho-841208

ABSTRACT

COVID-19, caused by SARS-CoV-2, lacks effective therapeutics. Additionally, no antiviral drugs or vaccines were developed against the closely related coronavirus, SARS-CoV-1 or MERS-CoV, despite previous zoonotic outbreaks. To identify starting points for such therapeutics, we performed a large-scale screen of electrophile and non-covalent fragments through a combined mass spectrometry and X-ray approach against the SARS-CoV-2 main protease, one of two cysteine viral proteases essential for viral replication. Our crystallographic screen identified 71 hits that span the entire active site, as well as 3 hits at the dimer interface. These structures reveal routes to rapidly develop more potent inhibitors through merging of covalent and non-covalent fragment hits; one series of low-reactivity, tractable covalent fragments were progressed to discover improved binders. These combined hits offer unprecedented structural and reactivity information for on-going structure-based drug design against SARS-CoV-2 main protease.


Subject(s)
Betacoronavirus/chemistry , Cysteine Endopeptidases/chemistry , Peptide Fragments/chemistry , Viral Nonstructural Proteins/chemistry , Betacoronavirus/enzymology , Binding Sites , Catalytic Domain , Coronavirus 3C Proteases , Crystallography, X-Ray , Cysteine Endopeptidases/metabolism , Drug Design , Mass Spectrometry , Models, Molecular , Peptide Fragments/metabolism , Protein Conformation , SARS-CoV-2 , Small Molecule Libraries/chemistry , Small Molecule Libraries/metabolism , Static Electricity , Viral Nonstructural Proteins/metabolism
19.
J Comput Aided Mol Des ; 34(12): 1237-1259, 2020 12.
Article in English | MEDLINE | ID: covidwho-841071

ABSTRACT

Computational protein-ligand docking is well-known to be prone to inaccuracies in input receptor structures, and it is challenging to obtain good docking results with computationally predicted receptor structures (e.g. through homology modeling). Here we introduce a fragment-based docking method and test if it reduces requirements on the accuracy of an input receptor structures relative to non-fragment docking approaches. In this method, small rigid fragments are docked first using AutoDock Vina to generate a large number of favorably docked poses spanning the receptor binding pocket. Then a graph theory maximum clique algorithm is applied to find combined sets of docked poses of different fragment types onto which the complete ligand can be properly aligned. On the basis of these alignments, possible binding poses of complete ligand are determined. This docking method is first tested for bound docking on a series of Cytochrome P450 (CYP450) enzyme-substrate complexes, in which experimentally determined receptor structures are used. For all complexes tested, ligand poses of less than 1 Å root mean square deviations (RMSD) from the actual binding positions can be recovered. Then the method is tested for unbound docking with modeled receptor structures for a number of protein-ligand complexes from different families including the very recent severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) protease. For all complexes, poses with RMSD less than 3 Å from actual binding positions can be recovered. Our results suggest that for docking with approximately modeled receptor structures, fragment-based methods can be more effective than common complete ligand docking approaches.


Subject(s)
Betacoronavirus/enzymology , Coronavirus Infections/drug therapy , Cysteine Endopeptidases/drug effects , Molecular Docking Simulation , Pandemics , Pneumonia, Viral/drug therapy , Viral Nonstructural Proteins/drug effects , ATPases Associated with Diverse Cellular Activities/chemistry , ATPases Associated with Diverse Cellular Activities/metabolism , COVID-19 , Coronavirus 3C Proteases , Cysteine Endopeptidases/chemistry , Cysteine Endopeptidases/metabolism , Cytochrome P-450 Enzyme System/chemistry , Cytochrome P-450 Enzyme System/metabolism , DNA-Binding Proteins/chemistry , DNA-Binding Proteins/metabolism , Humans , Ligands , Models, Chemical , Models, Molecular , Molecular Chaperones/chemistry , Molecular Chaperones/metabolism , Peptide Fragments/chemistry , Peptide Fragments/metabolism , Protein Binding , Protein Conformation , Receptors, G-Protein-Coupled/chemistry , Receptors, G-Protein-Coupled/metabolism , SARS-CoV-2 , Transcription Factors/chemistry , Transcription Factors/metabolism , Viral Nonstructural Proteins/chemistry , Viral Nonstructural Proteins/metabolism
20.
Comput Biol Med ; 126: 104046, 2020 11.
Article in English | MEDLINE | ID: covidwho-837907

ABSTRACT

Coronavirus Disease 2019 (COVID-19) is an infectious illness caused by Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2), originally identified in Wuhan, China (December 2019) and has since expanded into a pandemic. Here, we investigate metabolites present in several common spices as possible inhibitors of COVID-19. Specifically, 32 compounds isolated from 14 cooking seasonings were examined as inhibitors for SARS-CoV-2 main protease (Mpro), which is required for viral multiplication. Using a drug discovery approach to identify possible antiviral leads, in silico molecular docking studies were performed. Docking calculations revealed a high potency of salvianolic acid A and curcumin as Mpro inhibitors with binding energies of -9.7 and -9.2 kcal/mol, respectively. Binding mode analysis demonstrated the ability of salvianolic acid A and curcumin to form nine and six hydrogen bonds, respectively with amino acids proximal to Mpro's active site. Stabilities and binding affinities of the two identified natural spices were calculated over 40 ns molecular dynamics simulations and compared to an antiviral protease inhibitor (lopinavir). Molecular mechanics-generalized Born surface area energy calculations revealed greater salvianolic acid A affinity for the enzyme over curcumin and lopinavir with energies of -44.8, -34.2 and -34.8 kcal/mol, respectively. Using a STRING database, protein-protein interactions were identified for salvianolic acid A included the biochemical signaling genes ACE, MAPK14 and ESR1; and for curcumin, EGFR and TNF. This study establishes salvianolic acid A as an in silico natural product inhibitor against the SARS-CoV-2 main protease and provides a promising inhibitor lead for in vitro enzyme testing.


Subject(s)
Betacoronavirus/enzymology , Caffeic Acids/chemistry , Coronavirus Infections/drug therapy , Curcumin/chemistry , Cysteine Endopeptidases , Drug Discovery , Lactates/chemistry , Molecular Docking Simulation , Molecular Dynamics Simulation , Pneumonia, Viral/drug therapy , Protease Inhibitors/chemistry , Viral Nonstructural Proteins , COVID-19 , Caffeic Acids/therapeutic use , Coronavirus 3C Proteases , Coronavirus Infections/enzymology , Curcumin/therapeutic use , Cysteine Endopeptidases/chemistry , Humans , Lactates/therapeutic use , Pandemics , Pneumonia, Viral/enzymology , Protease Inhibitors/therapeutic use , SARS-CoV-2 , Thermodynamics , Viral Nonstructural Proteins/antagonists & inhibitors , Viral Nonstructural Proteins/chemistry
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