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1.
J Mol Liq ; 354: 118901, 2022 May 15.
Article in English | MEDLINE | ID: covidwho-1730001

ABSTRACT

Since the commencement of the novel Coronavirus, the disease has quickly turned into a worldwide crisis so that there has been growing attention in discovering possible hit compounds for tackling this pandemic. Discovering standard treatment strategies is a serious challenge because little information is available about this emerged infectious virus. Regarding the high impact of time, applying computational procedures to choose promising drugs from a catalog of licensed medications provides a precious chance for combat against the life-threatening disorder of COVID-19. Molecular dynamics (MD) simulation is a promising approach for assessing the binding affinity of ligand-receptor as well as observing the conformational trajectory of docked complexes over time. Given that many computational studies are performed using MD along with the molecular docking on various candidates as antiviral inhibitors of COVID-19 protease, there is a demand to conduct a comprehensive review of the most important studies to reveal and compare the potential introduced agents that this study covers this defect. In this context, the present review intends to prepare an overview of these studies by considering RMSD, RMSF, radius of gyration, binding free energy, and Solvent-Accessible Surface Area (SASA) as effective parameters for evaluation. The outcomes will offer a road map for adjusting antiviral inhibitors, which can facilitate the selection and development of drug candidates for use in the medical therapy. Finally, the molecular modeling approaches rendered by this study may be valuable for future computational studies.

2.
J Mol Graph Model ; 110: 108042, 2022 01.
Article in English | MEDLINE | ID: covidwho-1517349

ABSTRACT

We have studied the non-covalent interaction between PF-07321332 and SARS-CoV-2 main protease at the atomic level using a computational approach based on extensive molecular dynamics simulations with explicit solvent. PF-07321332, whose chemical structure has been recently disclosed, is a promising oral antiviral clinical candidate with well-established anti-SARS-CoV-2 activity in vitro. The drug, currently in phase III clinical trials in combination with ritonavir, relies on the electrophilic attack of a nitrile warhead to the catalytic cysteine of the protease. Nonbonded interaction between the inhibitor and the residues of the binding pocket, as well as with water molecules on the protein surface, have been characterized using two different force fields and the two possible protonation states of the main protease catalytic dyad HIS41-CYS145. When the catalytic dyad is in the neutral state, the non-covalent binding is likely to be stronger. Molecular dynamics simulations seems to lend support for an inhibitory mechanism in two steps: a first non-covalent addition with the dyad in neutral form and then the formation of the thiolate-imidazolium ion pair and the ligand relocation for finalising the electrophilic attack.


Subject(s)
COVID-19 , SARS-CoV-2 , Antiviral Agents/therapeutic use , Coronavirus 3C Proteases , Humans , Lactams , Leucine , Molecular Docking Simulation , Molecular Dynamics Simulation , Nitriles , Proline , Protease Inhibitors
3.
Heliyon ; 7(10): e08220, 2021 Oct.
Article in English | MEDLINE | ID: covidwho-1482617

ABSTRACT

In order to evaluate the interactions between a potential drug candidate like inhibitor N3 and the residues in substrate binding site of SARS-CoV-2 main protease ( M pro ), we used molecular docking and dynamics simulations. The structural features describing the degrees of folding states of M pro formed by beta-barrels and alpha-helices were analyzed by means of root mean square deviation, root mean square fluctuation, radius of gyration, residue velocity, H-bonding, dihedral angle distributions and radial distribution function. All of the residues forming ligand binding domain (LBD) of M pro lie within the allowed region of the dihedral angle distributions as observed from the equilibrating best pose of M pro -N3 system. Sharp peaks of radial distribution function (RDF) for H-bonding atom pairs (about 2 Å radial distance apart) describe the strong interactions between inhibitor and SARS-CoV-2 M pro . During MD simulations, HSE163 has the lowest residue speed offering a sharp RDF peak whereas GLN192 has the highest residue speed resulting a flat RDF peak for the H-bonding atom pairs of M pro -N3 system. Along with negative values of coulombic and Lenard-Jones energies, MM/PBSA free energy of binding contributed by the non-covalent interactions between M pro and N3 has been obtained to be -19.45 ± 3.6 kcal/mol. These physical parameters demonstrate the binding nature of an inhibitor in M pro -LBD. This study will be helpful in evaluating the drug candidates which are expected to inhibit the SARS-CoV-2 structural proteins.

4.
Adv Redox Res ; 3: 100021, 2021 Dec.
Article in English | MEDLINE | ID: covidwho-1458657

ABSTRACT

SARS-CoV-2 main protease is a possible target for protection against viral infection. This study examined the inhibitory effect of food phytochemicals on the main protease of SARS-CoV-2 by determining a cleaved product after chromatographic separation. First, 37 phytochemicals, including glycosides and metabolites, were screened at 20 µM; epigallocatechin gallate, myricetin, theaflavin, herbacetin, piceatannol, myricitrin, and isothiocyanates inhibited the enzyme in varying degrees. The IC50 values were estimated from 0.4 to 33.3 µM against the 0.5-µM enzyme. The dose-dependent adduction of epigallocatechin gallate and myricetin was confirmed by quinone staining of protein blotted onto a membrane. The enzyme activity was decreased by increasing the concentration of the two phytochemicals, accompanied by increasing the respective adducted molecule estimated by intact mass spectrometry. Reduced glutathione canceled the formation of conjugate and the inhibitory effect of epigallocatechin gallate or myricetin on the enzyme, suggesting that the formation of the quinone moiety in the phytochemicals is critical for the inhibition. The covalent binding of epigallocatechin gallate or myricetin to the cysteine residue at the active site was confirmed by analyzing peptides from the chymotrypsin-digested main protease.

5.
J Med Virol ; 93(5): 2722-2734, 2021 05.
Article in English | MEDLINE | ID: covidwho-1196526

ABSTRACT

The 21st century has witnessed three outbreaks of coronavirus (CoVs) infections caused by severe acute respiratory syndrome (SARS)-CoV, Middle East respiratory syndrome (MERS)-CoV, and SARS-CoV-2. Coronavirus disease 2019 (COVID-19), caused by SARS-CoV-2, spreads rapidly and since the discovery of the first COVID-19 infection in December 2019, has caused 1.2 million deaths worldwide and 226,777 deaths in the United States alone. The high amino acid similarity between SARS-CoV and SARS-CoV-2 viral proteins supports testing therapeutic molecules that were designed to treat SARS infections during the 2003 epidemic. In this review, we provide information on possible COVID-19 treatment strategies that act via inhibition of the two essential proteins of the virus, 3C-like protease (3CLpro ) or papain-like protease (PLpro ).


Subject(s)
Antiviral Agents/therapeutic use , COVID-19/drug therapy , Viral Proteases/drug effects , COVID-19/epidemiology , Coronavirus 3C Proteases/chemistry , Coronavirus 3C Proteases/drug effects , Coronavirus 3C Proteases/genetics , Coronavirus Papain-Like Proteases/chemistry , Coronavirus Papain-Like Proteases/drug effects , Coronavirus Papain-Like Proteases/genetics , Humans , Middle East Respiratory Syndrome Coronavirus , Protease Inhibitors/therapeutic use , SARS-CoV-2/genetics , SARS-CoV-2/metabolism , Viral Nonstructural Proteins/chemistry , Viral Nonstructural Proteins/genetics
6.
Chem Phys Lett ; 750: 137489, 2020 Jul.
Article in English | MEDLINE | ID: covidwho-1025637

ABSTRACT

We have applied a computational strategy, using a combination of virtual screening, docking and molecular dynamics techniques, aimed at identifying possible lead compounds for the non-covalent inhibition of the main protease 3CLpro of the SARS-CoV2 Coronavirus. Based on the X-ray structure (PDB code: 6LU7), ligands were generated using a multimodal structure-based design and then docked to the monomer in the active state. Docking calculations show that ligand-binding is strikingly similar in SARS-CoV and SARS-CoV2 main proteases. The most potent docked ligands are found to share a common binding pattern with aromatic moieties connected by rotatable bonds in a pseudo-linear arrangement.

7.
J Biomol Struct Dyn ; 40(11): 5112-5127, 2022 Jul.
Article in English | MEDLINE | ID: covidwho-1007468

ABSTRACT

Novel coronavirus (COVID-19) responsible for viral pneumonia which emerged in late 2019 has badly affected the world. No clinically proven drugs are available yet as the targeted therapeutic agents for the treatment of this disease. The viral main protease which helps in replication and transcription inside the host can be an effective drug target. In the present study, we aimed to discover the potential of ß-adrenoceptor agonists and adenosine deaminase inhibitors which are used in asthma and cancer/inflammatory disorders, respectively, as repurposing drugs against protease inhibitor by ligand-based and structure-based virtual screening using COVID-19 protease-N3 complex. The AARRR pharmacophore model was used to screen a set of 22,621 molecules to obtain hits, which were subjected to high-throughput virtual screening. Extra precision docking identified four top-scored molecules such as +/--fenoterol, FR236913 and FR230513 with lower binding energy from both categories. Docking identified three major hydrogen bonds with Gly143, Glu166 and Gln189 residues. 100 ns MD simulation was performed for four top-scored molecules to analyze the stability, molecular mechanism and energy requirements. MM/PBSA energy calculation suggested that van der Waals and electrostatic energy components are the main reasons for the stability of complexes. Water-mediated hydrogen bonds between protein-ligand and flexibility of the ligand are found to be responsible for providing extra stability to the complexes. The insights gained from this combinatorial approach can be used to design more potent and bio-available protease inhibitors against novel coronavirus.Communicated by Ramaswamy H. Sarma.


Subject(s)
Adenosine Deaminase Inhibitors , Adrenergic Agonists , Antiviral Agents , Coronavirus 3C Proteases , SARS-CoV-2 , Adenosine Deaminase Inhibitors/chemistry , Adenosine Deaminase Inhibitors/pharmacology , Adrenergic Agonists/chemistry , Adrenergic Agonists/pharmacology , Antiviral Agents/chemistry , Antiviral Agents/pharmacology , COVID-19/drug therapy , Coronavirus 3C Proteases/antagonists & inhibitors , Drug Repositioning , Humans , Ligands , Molecular Docking Simulation , Molecular Dynamics Simulation , Protease Inhibitors/chemistry , Protease Inhibitors/pharmacology , Receptors, Adrenergic , SARS-CoV-2/drug effects
8.
Phytother Res ; 34(12): 3137-3147, 2020 Dec.
Article in English | MEDLINE | ID: covidwho-969744

ABSTRACT

At the end of 2019, a novel flu-like coronavirus named COVID-19 (coronavirus disease 2019) was recognized by World Health Organization. No specific treatments exist for COVID-19 at this time. New evidence suggests that therapeutic options focusing on antiviral agents may alleviate COVID-19 symptoms as well as those that lead to the decrease in the inflammatory responses. Flavonoids, as phenolic compounds, have attracted considerable attention due to their various biological properties. In this review, the promising effects and possible mechanisms of action of naringenin, a citrus-derived flavonoid, against COVID-19 were discussed. We searched PubMed/Medline, Science direct, Scopus, and Google Scholar databases up to March 2020 using the definitive keywords. The evidence reviewed here indicates that naringenin might exert therapeutic effects against COVID-19 through the inhibition of COVID-19 main protease, 3-chymotrypsin-like protease (3CLpro), and reduction of angiotensin converting enzyme receptors activity. One of the other mechanisms by which naringenin might exert therapeutic effects against COVID-19 is, at least partly, by attenuating inflammatory responses. The antiviral activity of the flavanone naringenin against some viruses has also been reported. On the whole, the favorable effects of naringenin lead to a conclusion that naringenin may be a promising treatment strategy against COVID-19.


Subject(s)
Anti-Inflammatory Agents/therapeutic use , Antiviral Agents/therapeutic use , Flavanones/therapeutic use , Animals , Antiviral Agents/pharmacology , COVID-19/drug therapy , COVID-19/metabolism , Flavanones/pharmacology , Humans , SARS-CoV-2/drug effects
9.
J Biomol Struct Dyn ; 40(8): 3706-3710, 2022 05.
Article in English | MEDLINE | ID: covidwho-939482

ABSTRACT

The ongoing outbreak of Coronavirus disease 2019 (COVID-19) is a matter of great concern. Although the mortality rate caused by this virus is less than that of SARS and MERS, it is showing higher efficacy in terms of human-to-human transmission. Several strategies have been taken by scientists and researchers worldwide to combat this virus. Numerous phytochemicals and synthesized chemicals are under incessant inspection to obtain a potent anti-covid drug. Since, till now no precise therapy is available for covid patients, researchers are trying to categorize all possible anti-covid substances. Repurposing of drugs and combined drug therapy are becoming popular in treating such viral diseases. In this study, we are proposing the repurposing of three chemicals-Dextromethorphan, Prednisolone and Dexamethasone as anti-covid agents. We have used the tertiary structure of Coronavirus main protease (Mpro) with PDB ID 6LU7 as the target protein in this analysis. Molecular docking and dynamics study further revealed their synergistic effect against the COVID-19 protease protein.Communicated by Ramaswamy H. Sarma.


Subject(s)
COVID-19 , Common Cold , COVID-19/drug therapy , Dexamethasone/pharmacology , Dextromethorphan , Humans , Molecular Docking Simulation , Molecular Dynamics Simulation , Peptide Hydrolases , Prednisolone/pharmacology , Protease Inhibitors , SARS-CoV-2
10.
J Biomol Struct Dyn ; 39(9): 3428-3434, 2021 06.
Article in English | MEDLINE | ID: covidwho-154869

ABSTRACT

The 2019-novel coronavirus (nCoV) has caused a global health crisis by causing coronavirus disease-19 (COVID-19) pandemic in the human population. The unavailability of specific vaccines and anti-viral drug for nCoV, science demands sincere efforts in the field of drug design and discovery for COVID-19. The novel coronavirus main protease (SARS-CoV-2 Mpro) play a crucial role during the disease propagation, and hence SARS-CoV-2 Mpro represents as a drug target for the drug discovery. Herein, we have applied bioinformatics approach for screening of chemical compounds from Indian spices as potent inhibitors of SARS-CoV-2 main protease (PDBID: 6Y84). The structure files of Indian spices chemical compounds were taken from PubChem database or Zinc database and screened by molecular docking, by using AutoDock-4.2, MGLTools-1.5.6, Raccoon virtual screening tools. Top 04 hits based on their highest binding affinity were analyzed. Carnosol exhibited highest binding affinity -8.2 Kcal/mol and strong and stable interactions with the amino acid residues present on the active site of SARS-CoV-2 Mpro. Arjunglucoside-I (-7.88 Kcal/mol) and Rosmanol (-7.99 Kcal/mol) also showed a strong and stable binding affinity with favourable ADME properties. These compounds on MD simulations for 50 ns shows strong hydrogen-bonding interactions with the protein active site and remains stable inside the active site. Our virtual screening results suggest that these small chemical molecules can be used as potential inhibitors against SARS-CoV-2 Mpro and may have an anti-viral effect on nCoV. However, further validation and investigation of these inhibitors against SARS-CoV-2 main protease are needed to claim their candidacy for clinical trials.Communicated by Ramaswamy H. Sarma.


Subject(s)
COVID-19 , Pharmaceutical Preparations , Humans , Molecular Docking Simulation , Peptide Hydrolases , Protease Inhibitors/pharmacology , SARS-CoV-2 , Spices
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