scholarly journals Phenothiazines as dual inhibitors of SARS-CoV-2 main protease and COVID-19 inflammation

2021 ◽  
Author(s):  
Katrina L Forrestall ◽  
Darcy E Burley ◽  
Meghan Kirsten Cash ◽  
Ian Pottie ◽  
Sultan Darvesh
Keyword(s):  
Viral Replication ◽  
Active Site ◽  
Acute Infection ◽  
Binding Energies ◽  
Neurotransmitter Receptors ◽  
Main Protease ◽  
Dual Action ◽  
Inhibition Constants ◽  
Anti Inflammatory ◽  
Essential Enzyme

COVID-19, caused by the severe acute respiratory coronavirus 2 (SARS-CoV-2) currently has no treatment for acute infection. The main protease (Mpro) of SARS-CoV-2 is an essential enzyme for viral replication and an attractive target for disease intervention. The phenothiazine moiety has demonstrated drug versatility for biological systems, including inhibition of butyrylcholinesterase, a property important in the cholinesterase anti-inflammatory cascade. Nineteen phenothiazine drugs were investigated using in silico modelling techniques to predict binding energies and inhibition constants (Ki values) with SARS-CoV-2 Mpro. Since most side-effects of phenothiazines are due to interactions with various neurotransmitter receptors and transporters, phenothiazines with few such interactions were also investigated. All compounds were found to bind to the active site of SARS-CoV-2 Mpro and showed Ki values ranging from 1.30 to 52.4 µM. Nine phenothiazines showed inhibition constants <10 µM. The compounds with limited interactions with neurotransmitter receptors and transporters showed micromolar (µM) Ki values. Docking results were compared with remdesivir and showed similar interactions with key residues Glu-166 and Gln-189 in the active site. This work has identified several phenothiazines with limited neurotransmitter receptor and transporter interactions and that may provide the dual action of inhibiting SARS-CoV-2 Mpro to prevent viral replication and promote the release of anti-inflammatory cytokines to curb viral-induced inflammation. These compounds are promising candidates for further investigation against SARS-CoV-2.

scholarly journals Discovery of Fungal Metabolites Bergenin, Quercitrin and Dihydroartemisinin as Potential Inhibitors Against Main Protease of SARS-CoV-2

2020 ◽  
Author(s):  
Ravi Patel ◽  
Akash Vanzara ◽  
Nimisha Patel ◽  
Ajit Vasava ◽  
Sachin Patil ◽  
...  
Keyword(s):  
Bioactive Compounds ◽  
Active Site ◽  
Electrostatic Interactions ◽  
Hydrophobic Interactions ◽  
Binding Energies ◽  
Crystallographic Structure ◽  
Medicinal Uses ◽  
Main Protease ◽  
Cyathus Stercoreus ◽  
Potential Inhibitors

Emergence of severe acute respiratory syndrome corona virus 2 (SARS-CoV-2) infection has given rise to COVID-19 pandemic, that is wreaking havoc worldwide. Therefore, there is an urgent need to find out novel drugs to combat SARS-CoV-2 infection. In this backdrop, the present study was aimed to assess potent bioactive compounds from different fungi as potential inhibitors of SARS-CoV-2 main protease (M<sup>pro</sup>) using an <i>in-silico</i> analysis. Nearly 118 bioactive compounds were extracted from <i>Dictyophora indusiata</i>, <i>Geassstrum triplex</i> and <i>Cyathus stercoreus </i>and identified using HR LC/MS analysis. Of which, only bergenin (<i>D. indusiata</i>), quercitrin (<i>G. triplex</i>) and dihydroartemisinin (<i>C. stercoreus</i>) were selected based on their medicinal uses, binding score and active site covered. The 6LU7, a protein crystallographic structure of SARS-CoV-2 M<sup>pro</sup>, was docked with bergenin, quercitrin and dihydroartemisinin using Autodock 4.2 and the binding energies obtained were -7.86, -10.29 and -7.20 kcal/mol, respectively. Bergenin, quercitrin and dihydroartemisinin formed hydrogen bond, electrostatic interactions and hydrophobic interactions with foremost active site amino acids THR190, GLU166, GLN189, GLY143, HIS163, HIS164, CYS145 and PHE140. Present investigation suggests that these three drugs may be used as alternative inhibitors against SARS-CoV-2 M<sup>pro</sup>. However, further research is necessary to assess <i>in vitro</i> potential of these drugs. To the best of our knowledge, present investigation reported these three bioactive compounds of fungal origin for the first time.

scholarly journals Zinc2+ ion inhibits SARS-CoV-2 main protease and viral replication in vitro

2021 ◽  
Vol 57 (78) ◽  
pp. 10083-10086
Author(s):  
Love Panchariya ◽  
Wajahat Ali Khan ◽  
Shobhan Kuila ◽  
Kirtishila Sonkar ◽  
Sibasis Sahoo ◽  
...  
Keyword(s):  
Enzyme Activity ◽  
Viral Replication ◽  
Active Site ◽  
Main Protease

Zn2+ binds to the active site of the SARS-CoV-2 main protease (Mpro), and inhibits enzyme activity and viral replication in vitro.

scholarly journals IN Silico Approach of Some Selected Honey Constituents as SARS-CoV-2 Main Protease (COVID-19) Inhibitors

2020 ◽  
Author(s):  
Heba Hashem
Keyword(s):  
Active Site ◽  
Life Cycles ◽  
High Binding Energy ◽  
Protease Inhibition ◽  
Enzyme Active Site ◽  
Therapeutic Drugs ◽  
Main Protease ◽  
The World ◽  
Essential Enzyme ◽  
The Way

<p>The huge attack of coronavirus disease 2019 (COVID-19) over all the world forces the researcher around the world to study the crystal structure of the main protease M<sup>pro</sup> ( 3-chymotrypsin-like cysteine enzyme) which is the essential enzyme for coronavirus processing the polyproteins and its life cycles. And by the way, the inhibition of this enzyme active site becomes the target of all scientists of drug discovery in order to overcome this disease. In this study, we have used the molecular modeling approach to evaluate the activity of different active compounds from honeybee and propolis to inhibit the presented sars-cov-2 main protease via Schrödinger Maestro v10.1. the presented study resulted in six main compounds possess high binding energy with the receptor active site of COVID-19 main protease. we hope this study being the way for honeybee constitution as an effective ligand for sars-cov-2 main protease inhibition and be in the medicinal study of anti-COVID-19 therapeutic drugs.</p>

scholarly journals Unusual zwitterionic catalytic site of SARS–CoV-2 main protease revealed by neutron crystallography

2020 ◽  
Vol 295 (50) ◽  
pp. 17365-17373 ◽  
Author(s):  
Daniel W. Kneller ◽  
Gwyndalyn Phillips ◽  
Kevin L. Weiss ◽  
Swati Pant ◽  
Qiu Zhang ◽  
...  
Keyword(s):  
Active Site ◽  
Direct Determination ◽  
Catalytic Site ◽  
Amino Acid Residues ◽  
Critical Question ◽  
Main Protease ◽  
Neutron Structure ◽  
Active Site Cavity ◽  
Ionizable Residues ◽  
Essential Enzyme

The main protease (3CL Mpro) from SARS–CoV-2, the etiological agent of COVID-19, is an essential enzyme for viral replication. 3CL Mpro possesses an unusual catalytic dyad composed of Cys145 and His41 residues. A critical question in the field has been what the protonation states of the ionizable residues in the substrate-binding active-site cavity are; resolving this point would help understand the catalytic details of the enzyme and inform rational drug development against this pernicious virus. Here, we present the room-temperature neutron structure of 3CL Mpro, which allowed direct determination of hydrogen atom positions and, hence, protonation states in the protease. We observe that the catalytic site natively adopts a zwitterionic reactive form in which Cys145 is in the negatively charged thiolate state and His41 is doubly protonated and positively charged, instead of the neutral unreactive state usually envisaged. The neutron structure also identified the protonation states, and thus electrical charges, of all other amino acid residues and revealed intricate hydrogen-bonding networks in the active-site cavity and at the dimer interface. The fine atomic details present in this structure were made possible by the unique scattering properties of the neutron, which is an ideal probe for locating hydrogen positions and experimentally determining protonation states at near-physiological temperature. Our observations provide critical information for structure-assisted and computational drug design, allowing precise tailoring of inhibitors to the enzyme's electrostatic environment.

scholarly journals A Survey of Inhibitors for the Main Protease of Coronaviruses with the Potential for Development of Broad-Spectrum Therapeutics

2021 ◽  
Vol 17 (4) ◽  
pp. 71-84
Author(s):  
Alyssa Sanders ◽  
Samuel Ricci ◽  
Sarah Uribe ◽  
Bridget Boyle ◽  
Brian Nepper ◽  
...  
Keyword(s):  
Severe Acute Respiratory Syndrome ◽  
Viral Replication ◽  
Broad Spectrum ◽  
Active Site ◽  
Human Life ◽  
Neuraminidase Inhibitor ◽  
Main Protease ◽  
The World ◽  
Potential Inhibitors

The coronaviruses plaguing humanity in the 21st century share much in common: a spontaneous route of origin from wild animals, a propensity to take human life, and, importantly, a highly conserved set of biological machinery necessary for viral replication. Most recently, the SARS-CoV-2 is decimating economies around the world and has claimed over two million human lives, reminding the world of a need for an effective drug against present and future coronaviruses. To date, attempts to repurpose clinically approved antiviral medications show minimal promise, highlighting the need for development of new antiviral drugs. Nucleotide analog inhibitors are a promising therapeutic candidate, but early data from clinical studies suggests these compounds have limited efficacy. However, novel compounds targeting the main protease responsible for critical steps in viral assembly are gaining considerable interest because they offer the potential for broad-spectrum coronavirus therapy. Here, we review the literature regarding potential inhibitors for the main protease of coronaviruses, especially SARS-CoV-2, analyze receptor-drug interactions, and draw conclusions about candidate inhibitors for future outbreaks. Promising candidates for development of a broad-spectrum coronavirus protease inhibitor include the neuraminidase inhibitor 3K, the peptidomimetic inhibitor 11a and 11b, the α-ketoamide inhibitor 13b, the aldehyde prodrug, and the phosphate prodrug developed by Pfizer. In silico and in vitro analyses have shown that these inhibitors strongly interact with the active site of the main protease, and to varying degrees, prevent viral replication via interactions with the largely conserved active site pockets. KEYWORDS: Severe Acute Respiratory Syndrome Coronavirus; Middle East Respiratory Syndrome Coronavirus; Severe Acute Respiratory Syndrome Coronavirus 2; Replicase Polypeptide; Protease; Neuraminidase Inhibitor; Peptidomimetic Inhibitor; α-Ketoamide Inhibitor; Molecular Docking

scholarly journals Discovery of Fungal Metabolites Bergenin, Quercitrin and Dihydroartemisinin as Potential Inhibitors Against Main Protease of SARS-CoV-2

2020 ◽  
Author(s):  
Ravi Patel ◽  
Akash Vanzara ◽  
Nimisha Patel ◽  
Ajit Vasava ◽  
Sachin Patil ◽  
...  
Keyword(s):  
Bioactive Compounds ◽  
Active Site ◽  
Electrostatic Interactions ◽  
Hydrophobic Interactions ◽  
Binding Energies ◽  
Crystallographic Structure ◽  
Medicinal Uses ◽  
Main Protease ◽  
Cyathus Stercoreus ◽  
Potential Inhibitors

Emergence of severe acute respiratory syndrome corona virus 2 (SARS-CoV-2) infection has given rise to COVID-19 pandemic, that is wreaking havoc worldwide. Therefore, there is an urgent need to find out novel drugs to combat SARS-CoV-2 infection. In this backdrop, the present study was aimed to assess potent bioactive compounds from different fungi as potential inhibitors of SARS-CoV-2 main protease (M<sup>pro</sup>) using an <i>in-silico</i> analysis. Nearly 118 bioactive compounds were extracted from <i>Dictyophora indusiata</i>, <i>Geassstrum triplex</i> and <i>Cyathus stercoreus </i>and identified using HR LC/MS analysis. Of which, only bergenin (<i>D. indusiata</i>), quercitrin (<i>G. triplex</i>) and dihydroartemisinin (<i>C. stercoreus</i>) were selected based on their medicinal uses, binding score and active site covered. The 6LU7, a protein crystallographic structure of SARS-CoV-2 M<sup>pro</sup>, was docked with bergenin, quercitrin and dihydroartemisinin using Autodock 4.2 and the binding energies obtained were -7.86, -10.29 and -7.20 kcal/mol, respectively. Bergenin, quercitrin and dihydroartemisinin formed hydrogen bond, electrostatic interactions and hydrophobic interactions with foremost active site amino acids THR190, GLU166, GLN189, GLY143, HIS163, HIS164, CYS145 and PHE140. Present investigation suggests that these three drugs may be used as alternative inhibitors against SARS-CoV-2 M<sup>pro</sup>. However, further research is necessary to assess <i>in vitro</i> potential of these drugs. To the best of our knowledge, present investigation reported these three bioactive compounds of fungal origin for the first time.

scholarly journals Do fever-relieving medicines have anti-COVID activity: an in silico insight

2021 ◽  
Vol 16 (4) ◽  
pp. 293-300
Author(s):  
Fahad Hassan Shah ◽  
Kyeong Ho Lim ◽  
Song Ja Kim
Keyword(s):  
Severe Acute Respiratory Syndrome ◽  
Active Site ◽  
Drug Repositioning ◽  
Receptor Binding Domain ◽  
Rna Dependent Rna Polymerase ◽  
Inhibitory Interaction ◽  
Essential Proteins ◽  
High Affinity ◽  
Main Protease ◽  
Anti Inflammatory

Aim: The present study was performed to determine the inhibitory interaction of fever-relieving medicines with severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) essential proteins. Materials & methods: Structure-based drug repositioning was performed using PYRX 0.9 and these drugs were directed toward the predicted active site of SARS-CoV-2 spike glycoprotein receptor-binding domain, main protease and RNA-dependent RNA polymerase. Results: Results showed that acetaminophen and naproxen have considerable inhibitory activity and show a high affinity for active residues of these proteins. The prediction of activity spectra for substances (PASS) studies showed that these drugs are anti-inflammatory, antiviral and immunostimulant. Conclusion: Hence, it is proven that these drugs have antiviral activity against SARS-CoV-2 and can stimulate the immune and anti-inflammatory response against this disease.

scholarly journals Facing COVID-19 Via Anti-Inflammatory Mechanism of Action: Molecular Docking and Pharmacokinetic Studies of Six Anti-Inflammatory Compounds Derived from Passiflora edulis

2021 ◽  
pp. 35-51
Author(s):  
Aristote Matondo ◽  
Jason T. Kilembe ◽  
Domaine T. Mwanangombo ◽  
Beaudrique M. Nsimba ◽  
Dani T. Mawete ◽  
...  
Keyword(s):  
Molecular Docking ◽  
Severe Case ◽  
Binding Energies ◽  
Inflammatory Activity ◽  
Pharmacokinetic Studies ◽  
Passiflora Edulis ◽  
Potential Inhibitor ◽  
Main Protease ◽  
Anti Inflammatory ◽  
Pharmacokinetic Behavior

Aim: In the most severe case of the COVID-19, there is an excessive production of proinflammatory cytokines, being the main cause of mortality and morbidity. The present study aims at assessing the potential inhibitor effect of six phytochemicals with anti-inflammatory activity derived from Passiflora edulis, against the SARS-CoV-2 main protease. Materials and Methods: Virtual screening by molecular docking (Autodock tool) was used to obtain the binding energies of ligand-protein complexes formed between each of the six ligands and the SARS-CoV-2 main protease. The six ligands were then submitted to ADME (absorption, distribution, metabolism and excretion) and toxicity analyses to understand their pharmacokinetic behavior, using SwissADME, preADMET and pkCSM webservers. Results: Four high-docking score compounds were identified (both flavonoids) as hits, with the trend: ligand 4 (quercetin, -8.2 kcal/mol ) > ligand 1 (chrysin, -8.0 kcal/mol) > ligand 2 (kaempferol, -7.9 kcal/mol) > ligand 3 (luteolin, -7.7 kcal/mol)> ligand 5 (harmol, -6.7 kcal/mol) > ligand 6 (harmine, -6.4 kcal/mol). The pharmacokinetic behavior of the six ligands revealed that they can be easily absorbed and have good permeability and bioavailability. The toxicity predictions of the six compounds from P. edulis which is an editable fruit confirm that they are safe. Conclusion: Several approaches are currently being used to tackle the COVID-19. Given the cytokine storm in the most severe case of the COVID-19, we adopted the strategy of combatting the disease by compounds that exhibit anti-inflammatory activity. The assessment of the efficiency of six phytochemicals from P. edulis against the SARS-CoV-2 Mpro and their pharmacokinetic profile revealed their potential inhibitor effect against the COVID-19 protein.

scholarly journals IN Silico Approach of Some Selected Honey Constituents as SARS-CoV-2 Main Protease (COVID-19) Inhibitors

2020 ◽  
Author(s):  
Heba Hashem
Keyword(s):  
Active Site ◽  
Life Cycles ◽  
High Binding Energy ◽  
Protease Inhibition ◽  
Enzyme Active Site ◽  
Therapeutic Drugs ◽  
Main Protease ◽  
The World ◽  
Essential Enzyme ◽  
The Way

<p>The huge attack of coronavirus disease 2019 (COVID-19) over all the world forces the researcher around the world to study the crystal structure of the main protease M<sup>pro</sup> ( 3-chymotrypsin-like cysteine enzyme) which is the essential enzyme for coronavirus processing the polyproteins and its life cycles. And by the way, the inhibition of this enzyme active site becomes the target of all scientists of drug discovery in order to overcome this disease. In this study, we have used the molecular modeling approach to evaluate the activity of different active compounds from honeybee and propolis to inhibit the presented sars-cov-2 main protease via Schrödinger Maestro v10.1. the presented study resulted in six main compounds possess high binding energy with the receptor active site of COVID-19 main protease. we hope this study being the way for honeybee constitution as an effective ligand for sars-cov-2 main protease inhibition and be in the medicinal study of anti-COVID-19 therapeutic drugs.</p>

scholarly journals IN Silico Approach of Some Selected Honey Constituents as SARS-CoV-2 Main Protease (COVID-19) Inhibitors

2020 ◽  
Author(s):  
Heba Hashem
Keyword(s):  
Active Site ◽  
Life Cycles ◽  
High Binding Energy ◽  
Protease Inhibition ◽  
Enzyme Active Site ◽  
Therapeutic Drugs ◽  
Main Protease ◽  
The World ◽  
Essential Enzyme ◽  
The Way

<p>The huge attack of coronavirus disease 2019 (COVID-19) over all the world forces the researcher around the world to study the crystal structure of the main protease M<sup>pro</sup> ( 3-chymotrypsin-like cysteine enzyme) which is the essential enzyme for coronavirus processing the polyproteins and its life cycles. And by the way, the inhibition of this enzyme active site becomes the target of all scientists of drug discovery in order to overcome this disease. In this study, we have used the molecular modeling approach to evaluate the activity of different active compounds from honeybee and propolis to inhibit the presented sars-cov-2 main protease via Schrödinger Maestro v10.1. the presented study resulted in six main compounds possess high binding energy with the receptor active site of COVID-19 main protease. we hope this study being the way for honeybee constitution as an effective ligand for sars-cov-2 main protease inhibition and be in the medicinal study of anti-COVID-19 therapeutic drugs.</p>

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