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1.
Int J Mol Sci ; 22(21)2021 Oct 29.
Article in English | MEDLINE | ID: covidwho-1488615

ABSTRACT

Coronavirus disease 2019 (COVID-19), caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has received global attention due to the serious threat it poses to public health. Since the outbreak in December 2019, millions of people have been affected and its rapid global spread has led to an upsurge in the search for treatment. To discover hit compounds that can be used alone or in combination with repositioned drugs, we first analyzed the pharmacokinetic and toxicological properties of natural products from Brazil's semiarid region. After, we analyzed the site prediction and druggability of the SARS-CoV-2 main protease (Mpro), followed by docking and molecular dynamics simulation. The best SARS-CoV-2 Mpro complexes revealed that other sites were accessed, confirming that our approach could be employed as a suitable starting protocol for ligand prioritization, reinforcing the importance of catalytic cysteine-histidine residues and providing new structural data that could increase the antiviral development mainly against SARS-CoV-2. Here, we selected 10 molecules that could be in vitro assayed in response to COVID-19. Two compounds (b01 and b02) suggest a better potential for interaction with SARS-CoV-2 Mpro and could be further studied.


Subject(s)
Biological Products/pharmacology , COVID-19/drug therapy , Coronavirus 3C Proteases/chemistry , Coronavirus 3C Proteases/drug effects , Drug Design , SARS-CoV-2/chemistry , SARS-CoV-2/drug effects , Antiviral Agents/chemistry , Antiviral Agents/pharmacology , Binding Sites , Drug Discovery/methods , Drug Repositioning , Humans , Ligands , Molecular Docking Simulation , Molecular Dynamics Simulation , Protein Conformation , Viral Nonstructural Proteins/chemistry , Viral Nonstructural Proteins/drug effects
2.
Sci Rep ; 11(1): 17915, 2021 09 09.
Article in English | MEDLINE | ID: covidwho-1402117

ABSTRACT

Coronavirus disease 2019 (Covid-19), caused by novel severe acute respiratory syndrome coronavirus (SARS-CoV-2), has come to the fore in Wuhan, China in December 2019 and has been spreading expeditiously all over the world due to its high transmissibility and pathogenicity. From the outbreak of COVID-19, many efforts are being made to find a way to fight this pandemic. More than 300 clinical trials are ongoing to investigate the potential therapeutic option for preventing/treating COVID-19. Considering the critical role of SARS-CoV-2 main protease (Mpro) in pathogenesis being primarily involved in polyprotein processing and virus maturation, it makes SARS-CoV-2 main protease (Mpro) as an attractive and promising antiviral target. Thus, in our study, we focused on SARS-CoV-2 main protease (Mpro), used machine learning algorithms and virtually screened small derivatives of anthraquinolone and quinolizine from PubChem that may act as potential inhibitor. Prioritisation of cavity atoms obtained through pharmacophore mapping and other physicochemical descriptors of the derivatives helped mapped important chemical features for ligand binding interaction and also for synergistic studies with molecular docking. Subsequently, these studies outcome were supported through simulation trajectories that further proved anthraquinolone and quinolizine derivatives as potential small molecules to be tested experimentally in treating COVID-19 patients.


Subject(s)
Anthraquinones/therapeutic use , Antiviral Agents/therapeutic use , COVID-19/drug therapy , Quinolizines/therapeutic use , SARS-CoV-2/drug effects , Computational Biology , Coronavirus 3C Proteases/antagonists & inhibitors , Drug Repositioning , Humans , Machine Learning , Molecular Docking Simulation , Molecular Dynamics Simulation , Viral Nonstructural Proteins/drug effects
3.
J Med Virol ; 93(7): 4258-4264, 2021 Jul.
Article in English | MEDLINE | ID: covidwho-1173823

ABSTRACT

The recent coronavirus disease 2019 (COVID-19), causing a global pandemic with devastating effects on healthcare and social-economic systems, has no special antiviral therapies available for human coronaviruses (CoVs). The severe acute respiratory syndrome coronavirus 2 (SARS-Cov-2) possesses a nonstructural protein (nsp14), with amino-terminal domain coding for proofreading exoribonuclease (ExoN) that is required for high-fidelity replication. The ability of CoVs during genome replication and transcription to proofread and exclude mismatched nucleotides has long hindered the development of anti-CoV drugs. The resistance of SARS-CoV-2 to antivirals, especially nucleoside analogs (NAs), shows the need to identify new CoV inhibition targets. Therefore, this review highlights the importance of nsp14-ExoN as a target for inhibition. Also, nucleoside analogs could be used in combination with existing anti-CoV therapeutics to target the proofreading mechanism.


Subject(s)
Antiviral Agents/pharmacology , COVID-19/drug therapy , Exoribonucleases/genetics , SARS-CoV-2/genetics , Viral Nonstructural Proteins/genetics , Virus Replication/drug effects , Exoribonucleases/drug effects , Exoribonucleases/metabolism , Genome, Viral/genetics , Humans , Methyltransferases/genetics , RNA Processing, Post-Transcriptional/physiology , RNA, Viral/genetics , SARS-CoV-2/drug effects , Viral Nonstructural Proteins/drug effects , Viral Nonstructural Proteins/metabolism , Virus Replication/physiology
4.
Curr Mol Med ; 22(1): 50-66, 2022.
Article in English | MEDLINE | ID: covidwho-1099962

ABSTRACT

The proteins of coronavirus are classified as non-structural, structural, and accessory. There are 16 non-structural viral proteins besides their precursors (1a and 1ab polyproteins). The non-structural proteins are named nsp1 to nsp16, and they act as enzymes, coenzymes, and binding proteins to facilitate the replication, transcription, and translation of the virus. The structural proteins are bound to the RNA in the nucleocapsid (N- protein) or to the lipid bilayer membrane of the viral envelope. The lipid bilayer proteins include the membrane protein (M), an envelope protein (E), and spike protein (S). Besides their role as structural proteins, they are essential for the host cells' binding and invasion. The SARS-CoV-2 contains six accessory proteins which participate in the viral replication, assembly and virus-host interactions. The SARS-CoV-2 accessory proteins are orf3a, orf6, orf7a, orf7b, orf8, and orf10. The functions of the SARS-CoV-2 are not well known, while the functions of their corresponding proteins in SARS-CoV are either well known or poorly studied. Recently, the Oxford University and Astrazeneca, Pfizer and BioNTech have made SARS-CoV-2 vaccines by targeting the spike protein gene. The US Food and Drug Administration (FDA) and the health authorities of the United Kingdom have approved and started conducting vaccinations using the Pfizer and BioNTech mRNA vaccine. Also, The FDA of the USA has approved the use of two monoclonal antibodies produced by Regeneron pharmaceuticals to target the spike protein for treating COVID-19. The SARS-CoV-2 proteins can be used for the diagnosis, as drug targets and in vaccination trials for COVID-19. In future COVID-19 research, more efforts should be made to elaborate the functions and structure of the SARS-CoV- 2 proteins so as to use them as targets for COVID-19 drugs and vaccines. Special attention should be paid to extensive research on the SARS-CoV-2 nsp3, orf8, and orf10.


Subject(s)
Antiviral Agents/pharmacology , COVID-19 Vaccines , COVID-19/prevention & control , SARS-CoV-2/chemistry , Viral Proteins/drug effects , Viral Proteins/immunology , Antibodies, Monoclonal/immunology , Antibodies, Monoclonal/therapeutic use , Antibodies, Viral/immunology , Antibodies, Viral/therapeutic use , Antigens, Viral/immunology , COVID-19/drug therapy , COVID-19/immunology , Drug Design , Humans , Immunotherapy , SARS-CoV-2/drug effects , SARS-CoV-2/immunology , Spike Glycoprotein, Coronavirus/immunology , Viral Nonstructural Proteins/drug effects , Viral Nonstructural Proteins/immunology , Viral Nonstructural Proteins/physiology , Viral Proteins/physiology , Viral Regulatory and Accessory Proteins/drug effects , Viral Regulatory and Accessory Proteins/immunology , Viral Regulatory and Accessory Proteins/physiology , Viral Structural Proteins/drug effects , Viral Structural Proteins/immunology , Viral Structural Proteins/physiology
5.
Biomed Pharmacother ; 133: 111035, 2021 Jan.
Article in English | MEDLINE | ID: covidwho-1060177

ABSTRACT

Outbreaks of severe acute respiratory syndrome coronavirus (SARS-CoV), Middle East respiratory syndrome coronavirus (MERS-CoV), and SARS-CoV-2 have produced high pathogenicity and mortality rates in human populations. However, to meet the increasing demand for treatment of these pathogenic coronaviruses, accelerating novel antiviral drug development as much as possible has become a public concern. Target-based drug development may be a promising approach to achieve this goal. In this review, the relevant features of potential molecular targets in human coronaviruses (HCoVs) are highlighted, including the viral protease, RNA-dependent RNA polymerase, and methyltransferases. Additionally, recent advances in the development of antivirals based on these targets are summarized. This review is expected to provide new insights and potential strategies for the development of novel antiviral drugs to treat SARS-CoV-2 infection.


Subject(s)
Antiviral Agents/therapeutic use , COVID-19/drug therapy , Viral Nonstructural Proteins/drug effects , Drug Delivery Systems , Drug Development , Humans
6.
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
7.
J Comput Aided Mol Des ; 34(12): 1219-1228, 2020 12.
Article in English | MEDLINE | ID: covidwho-754411

ABSTRACT

SARS-CoV-2 recently jumped species and rapidly spread via human-to-human transmission to cause a global outbreak of COVID-19. The lack of effective vaccine combined with the severity of the disease necessitates attempts to develop small molecule drugs to combat the virus. COVID19_GIST_HSA is a freely available online repository to provide solvation thermodynamic maps of COVID-19-related protein small molecule drug targets. Grid inhomogeneous solvation theory maps were generated using AmberTools cpptraj-GIST, 3D reference interaction site model maps were created with AmberTools rism3d.snglpnt and hydration site analysis maps were created using SSTMap code. The resultant data can be applied to drug design efforts: scoring solvent displacement for docking, rational lead modification, prioritization of ligand- and protein- based pharmacophore elements, and creation of water-based pharmacophores. Herein, we demonstrate the use of the solvation thermodynamic mapping data. It is hoped that this freely provided data will aid in small molecule drug discovery efforts to defeat SARS-CoV-2.


Subject(s)
Antiviral Agents/pharmacology , Betacoronavirus/drug effects , Coronavirus Infections/drug therapy , Drug Design , Drug Evaluation, Preclinical , Models, Chemical , Molecular Dynamics Simulation , Molecular Targeted Therapy , Pandemics , Pneumonia, Viral/drug therapy , Thermodynamics , Viral Nonstructural Proteins/drug effects , Antiviral Agents/chemistry , Betacoronavirus/chemistry , Binding Sites , COVID-19 , Catalytic Domain , Humans , Ligands , Models, Molecular , Protein Conformation , SARS-CoV-2 , Small Molecule Libraries , Structure-Activity Relationship , Viral Nonstructural Proteins/chemistry , Water
8.
OMICS ; 24(10): 568-580, 2020 10.
Article in English | MEDLINE | ID: covidwho-696599

ABSTRACT

Although the coronavirus disease 2019 (COVID-19) pandemic caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is wreaking havoc and resulting in mortality and morbidity across the planet, novel treatments are urgently needed. Drug repurposing offers an innovative approach in this context. We report here new findings on the in silico potential of several antimalarial drugs for repurposing against COVID-19. We conducted analyses by docking the compounds against two SARS-CoV-2-specific targets: (1) the receptor binding domain spike protein and (2) the main protease of the virus (MPro) using the Schrödinger software. Importantly, the docking analysis revealed that doxycycline (DOX) showed the most effective binding to the spike protein of SARS-CoV-2, whereas halofantrine and mefloquine bound effectively with the main protease among the antimalarial drugs evaluated in the present study. The in silico approach reported here suggested that DOX could potentially be a good candidate for repurposing for COVID-19. In contrast, to decipher the actual potential of DOX and halofantrine against COVID-19, further in vitro and in vivo studies are called for. Drug repurposing warrants consideration as a viable research and innovation avenue as planetary health efforts to fight the COVID-19 continue.


Subject(s)
Antimalarials/pharmacology , Antiviral Agents/pharmacology , Betacoronavirus/drug effects , Coronavirus Infections/drug therapy , Drug Repositioning/methods , Pneumonia, Viral/drug therapy , Antimalarials/chemistry , Antiviral Agents/chemistry , Betacoronavirus/chemistry , Binding Sites , COVID-19 , Computer Simulation , Coronavirus 3C Proteases , Coronavirus Infections/epidemiology , Coronavirus Infections/virology , Cysteine Endopeptidases/chemistry , Cysteine Endopeptidases/drug effects , Doxycycline/chemistry , Doxycycline/pharmacology , Drug Evaluation, Preclinical , Humans , Molecular Docking Simulation , Pandemics , Pneumonia, Viral/epidemiology , Pneumonia, Viral/virology , SARS-CoV-2 , Spike Glycoprotein, Coronavirus/chemistry , Spike Glycoprotein, Coronavirus/drug effects , Viral Nonstructural Proteins/chemistry , Viral Nonstructural Proteins/drug effects
9.
Comput Biol Med ; 124: 103936, 2020 09.
Article in English | MEDLINE | ID: covidwho-679767

ABSTRACT

Virtual screening of phytochemicals was performed through molecular docking, simulations, in silico ADMET and drug-likeness prediction to identify the potential hits that can inhibit the effects of SARS-CoV-2. Considering the published literature on medicinal importance, 154 phytochemicals with analogous structure from limonoids and triterpenoids were selected to search potential inhibitors for the five therapeutic protein targets of SARS-CoV-2, i.e., 3CLpro (main protease), PLpro (papain-like protease), SGp-RBD (spike glycoprotein-receptor binding domain), RdRp (RNA dependent RNA polymerase) and ACE2 (angiotensin-converting enzyme 2). The in silico computational results revealed that the phytochemicals such as glycyrrhizic acid, limonin, 7-deacetyl-7-benzoylgedunin, maslinic acid, corosolic acid, obacunone and ursolic acid were found to be effective against the target proteins of SARS-CoV-2. The protein-ligand interaction study revealed that these phytochemicals bind with the amino acid residues at the active site of the target proteins. Therefore, the core structure of these potential hits can be used for further lead optimization to design drugs for SARS-CoV-2. Also, the medicinal plants containing these phytochemicals like licorice, neem, tulsi, citrus and olives can be used to formulate suitable therapeutic approaches in traditional medicines.


Subject(s)
Antiviral Agents/pharmacology , Betacoronavirus/chemistry , Betacoronavirus/drug effects , Coronavirus Infections/drug therapy , Coronavirus Infections/virology , Limonins/pharmacology , Pneumonia, Viral/drug therapy , Pneumonia, Viral/virology , Triterpenes/pharmacology , Angiotensin-Converting Enzyme 2 , Antiviral Agents/chemistry , Antiviral Agents/pharmacokinetics , Binding Sites , COVID-19 , Computational Biology , Computer Simulation , Coronavirus RNA-Dependent RNA Polymerase , Drug Evaluation, Preclinical , Host Microbial Interactions/drug effects , Humans , Limonins/chemistry , Limonins/pharmacokinetics , Molecular Docking Simulation , Pandemics , Peptidyl-Dipeptidase A/chemistry , Peptidyl-Dipeptidase A/drug effects , Phytochemicals/chemistry , Phytochemicals/pharmacokinetics , Phytochemicals/pharmacology , RNA-Dependent RNA Polymerase/chemistry , RNA-Dependent RNA Polymerase/drug effects , SARS-CoV-2 , Spike Glycoprotein, Coronavirus/chemistry , Spike Glycoprotein, Coronavirus/drug effects , Triterpenes/chemistry , Triterpenes/pharmacokinetics , Viral Nonstructural Proteins/chemistry , Viral Nonstructural Proteins/drug effects , Viral Proteins/chemistry , Viral Proteins/drug effects
10.
Chaos ; 30(6): 061102, 2020 Jun.
Article in English | MEDLINE | ID: covidwho-628595

ABSTRACT

There is an urgent necessity of effective medication against severe acute respiratory syndrome coronavirus 2 (SARS CoV-2), which is producing the COVID-19 pandemic across the world. Its main protease (Mpro) represents an attractive pharmacological target due to its involvement in essential viral functions. The crystal structure of free Mpro shows a large structural resemblance with the main protease of SARS CoV (nowadays known as SARS CoV-1). Here, we report that average SARS CoV-2 Mpro is 1900% more sensitive than SARS CoV-1 Mpro in transmitting tiny structural changes across the whole protein through long-range interactions. The largest sensitivity of Mpro to structural perturbations is located exactly around the catalytic site Cys-145 and coincides with the binding site of strong inhibitors. These findings, based on a simplified representation of the protein as a residue network, may help in designing potent inhibitors of SARS CoV-2 Mpro.


Subject(s)
Betacoronavirus/metabolism , Catalytic Domain/drug effects , Coronavirus Infections/drug therapy , Cysteine Endopeptidases/metabolism , Pneumonia, Viral/drug therapy , Protease Inhibitors/pharmacology , Viral Nonstructural Proteins/metabolism , Amino Acid Sequence , Binding Sites/drug effects , COVID-19 , Coronavirus 3C Proteases , Crystallography, X-Ray , Cysteine Endopeptidases/drug effects , Drug Design , Humans , Pandemics , SARS Virus/metabolism , SARS-CoV-2 , Viral Nonstructural Proteins/drug effects
11.
Med Hypotheses ; 140: 109755, 2020 Jul.
Article in English | MEDLINE | ID: covidwho-116951

ABSTRACT

The SARS-CoV-2 virus has spread around the world. At this time, there is no vaccine that can help people prevent the spread of coronavirus. We are proposing amantadine as a drug that can be used to mitigate the effects of the virus. It is demonstrated by docking models how amantadine can exert its action on Coronavirus viroporin E.


Subject(s)
Amantadine/therapeutic use , Coronavirus Infections/drug therapy , Pneumonia, Viral/drug therapy , Viral Envelope Proteins/chemistry , Betacoronavirus , COVID-19 , Coronavirus Envelope Proteins , Humans , Ion Channels/chemistry , Ion Channels/drug effects , Ligands , Molecular Docking Simulation , Pandemics , Protein Conformation , SARS-CoV-2 , Viral Nonstructural Proteins/chemistry , Viral Nonstructural Proteins/drug effects , Viroporin Proteins
12.
Bioinformatics ; 36(11): 3295-3298, 2020 06 01.
Article in English | MEDLINE | ID: covidwho-27689

ABSTRACT

MOTIVATION: Since December 2019, the newly identified coronavirus SARS-CoV-2 has caused a massive health crisis worldwide and resulted in over 70 000 COVID-19 infections so far. Clinical drugs targeting SARS-CoV-2 are urgently needed to decrease the high fatality rate of confirmed COVID-19 patients. Traditional de novo drug discovery needs more than 10 years, so drug repurposing seems the best option currently to find potential drugs for treating COVID-19. RESULTS: Compared with traditional non-covalent drugs, covalent drugs have attracted escalating attention recent years due to their advantages in potential specificity upon careful design, efficiency and patient burden. We recently developed a computational protocol named as SCAR (steric-clashes alleviating receptors) for discovering covalent drugs. In this work, we used the SCAR protocol to identify possible covalent drugs (approved or clinically tested) targeting the main protease (3CLpro) of SARS-CoV-2. We identified 11 potential hits, among which at least six hits were exclusively enriched by the SCAR protocol. Since the preclinical or clinical information of these identified drugs is already available, they might be ready for being clinically tested in the treatment of COVID-19. CONTACT: senliu.ctgu@gmail.com.


Subject(s)
Betacoronavirus , Coronavirus Infections , Coronavirus , Cysteine Endopeptidases , Drug Delivery Systems , Pandemics , Pneumonia, Viral , SARS Virus , Viral Nonstructural Proteins , Betacoronavirus/drug effects , COVID-19 , Coronavirus 3C Proteases , Coronavirus Infections/drug therapy , Coronavirus Infections/enzymology , Cysteine Endopeptidases/drug effects , Humans , Peptide Hydrolases/drug effects , Pneumonia, Viral/drug therapy , Pneumonia, Viral/enzymology , SARS-CoV-2 , Viral Nonstructural Proteins/drug effects
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