scholarly journals Inhibition of SARS-CoV-2 Main Protease: A Repurposing Study That Targets the Dimer Interface of the Protein

2020 ◽  
Author(s):  
Hanife Pekel ◽  
Metehan Ilter ◽  
Ozge Sensoy
Keyword(s):  
Drug Repurposing ◽  
Promising Candidate ◽  
Dimer Interface ◽  
Main Protease ◽  
Short Period ◽  
Holistic Understanding ◽  
Important Residue ◽  
Conformational Rearrangements ◽  
Dynamics Simulations ◽  
Catalytic Dyad

Coronavirus disease-2019 (COVID-19) was firstly reported in Wuhan, China, towards the end of 2019, and, unfortunately, within a short period of time, emerged as a pandemic. The spread and lethality rates of the COVID-19 have ignited studies that focus on the development of therapeutics for either treatment or prophylaxis purposes. In parallel, drug repurposing studies have also come into prominence. In this study, we aimed at having a holistic understanding of <br>conformational and dynamical changes induced by an experimentally characterized inhibitor on main protease (M-pro) which would enable the discovery of novel inhibitors. To this end, we performed molecular dynamics simulations using crystal structures of <i>apo</i> and α-ketoamide-13b-bound M-pro homodimer. Analysis of trajectories pertaining to <i>apo</i> M-pro revealed a new target site, which is located at the homodimer interface, next to the catalytic dyad. Thereafter, we performed ensemble-based virtual screening by exploiting the ZINC and DrugBank databases and identified three candidate molecules, namely eluxadoline, diosmin, and ZINC02948810 that could invoke local and global conformational rearrangements which were also elicited by α-ketoamide-13b on the catalytic dyad of M-pro. Furthermore, ZINC23881687 was also discerned as a promising candidate due to its interaction with catalytically important residues Glu166 and Ser1. Last but not least, we could find another candidate, namely ZINC20425029, whose mode of action was different. It modulated the dynamical properties of catalytically important residue, Ala285 rather than the catalytic dyad. As such, this study presents valuable findings that might be used in the development of novel therapeutics against SARS-CoV-2 M-pro. <br>

scholarly journals Inhibition of SARS-CoV-2 Main Protease: A Repurposing Study That Targets the Dimer Interface of the Protein

2020 ◽  
Author(s):  
Hanife Pekel ◽  
Metehan Ilter ◽  
Ozge Sensoy
Keyword(s):  
Drug Repurposing ◽  
Promising Candidate ◽  
Dimer Interface ◽  
Main Protease ◽  
Short Period ◽  
Holistic Understanding ◽  
Important Residue ◽  
Conformational Rearrangements ◽  
Dynamics Simulations ◽  
Catalytic Dyad

Coronavirus disease-2019 (COVID-19) was firstly reported in Wuhan, China, towards the end of 2019, and, unfortunately, within a short period of time, emerged as a pandemic. The spread and lethality rates of the COVID-19 have ignited studies that focus on the development of therapeutics for either treatment or prophylaxis purposes. In parallel, drug repurposing studies have also come into prominence. In this study, we aimed at having a holistic understanding of <br>conformational and dynamical changes induced by an experimentally characterized inhibitor on main protease (M-pro) which would enable the discovery of novel inhibitors. To this end, we performed molecular dynamics simulations using crystal structures of <i>apo</i> and α-ketoamide-13b-bound M-pro homodimer. Analysis of trajectories pertaining to <i>apo</i> M-pro revealed a new target site, which is located at the homodimer interface, next to the catalytic dyad. Thereafter, we performed ensemble-based virtual screening by exploiting the ZINC and DrugBank databases and identified three candidate molecules, namely eluxadoline, diosmin, and ZINC02948810 that could invoke local and global conformational rearrangements which were also elicited by α-ketoamide-13b on the catalytic dyad of M-pro. Furthermore, ZINC23881687 was also discerned as a promising candidate due to its interaction with catalytically important residues Glu166 and Ser1. Last but not least, we could find another candidate, namely ZINC20425029, whose mode of action was different. It modulated the dynamical properties of catalytically important residue, Ala285 rather than the catalytic dyad. As such, this study presents valuable findings that might be used in the development of novel therapeutics against SARS-CoV-2 M-pro. <br>

scholarly journals ABBV-744 as a potential inhibitor of SARS-CoV-2 main protease enzyme against COVID-19

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Zeynab Fakhar ◽  
Shama Khan ◽  
Suliman Y. AlOmar ◽  
Afrah Alkhuriji ◽  
Aijaz Ahmad
Keyword(s):  
Virtual Screening ◽  
Drug Repurposing ◽  
Pharmacophore Modeling ◽  
Binding Energies ◽  
Active Inhibitor ◽  
Lead Compounds ◽  
Protease Enzyme ◽  
Main Protease ◽  
Dynamics Simulations ◽  
Potential Inhibitors

AbstractA new pathogen severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has spread worldwide and become pandemic with thousands new deaths and infected cases globally. To address coronavirus disease (COVID-19), currently no effective drug or vaccine is available. This necessity motivated us to explore potential lead compounds by considering drug repurposing approach targeting main protease (Mpro) enzyme of SARS-CoV-2. This enzyme considered to be an attractive drug target as it contributes significantly in mediating viral replication and transcription. Herein, comprehensive computational investigations were performed to identify potential inhibitors of SARS-CoV-2 Mpro enzyme. The structure-based pharmacophore modeling was developed based on the co-crystallized structure of the enzyme with its biological active inhibitor. The generated hypotheses were applied for virtual screening based PhaseScore. Docking based virtual screening workflow was used to generate hit compounds using HTVS, SP and XP based Glide GScore. The pharmacological and physicochemical properties of the selected lead compounds were characterized using ADMET. Molecular dynamics simulations were performed to explore the binding affinities of the considered lead compounds. Binding energies revealed that compound ABBV-744 binds to the Mpro with strong affinity (ΔGbind −45.43 kcal/mol), and the complex is more stable in comparison with other protein–ligand complexes. Our study classified three best compounds which could be considered as promising inhibitors against main protease SARS-CoV-2 virus.

scholarly journals ABBV-744 and Onalespid as Potential Inhibitors of SARS-CoV-2 main Protease Enzyme: A Promising Therapeutics in COVID-19?

2020 ◽  
Author(s):  
Zeynab Fakhar ◽  
Shama Khan ◽  
Aijaz Ahmad
Keyword(s):  
Virtual Screening ◽  
Drug Repurposing ◽  
Pharmacophore Modeling ◽  
Binding Studies ◽  
Active Inhibitor ◽  
Lead Compounds ◽  
Protease Enzyme ◽  
Main Protease ◽  
Dynamics Simulations ◽  
Potential Inhibitors

Abstract A new pathogen severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has spread worldwide and become pandemic with thousands new deaths and infected cases globally. To address coronavirus disease (COVID-19), currently no effective drug or vaccine is available. This necessity motivated us to explore potential lead compounds by considering drug repurposing approach targeting main protease (Mpro) enzyme of SARS-CoV-2. This enzyme considered to be an attractive drug target as it contributes significantly in mediating viral replication and transcription. Herein, comprehensive computational investigations were performed to identify potential inhibitors of SARS-CoV-2 Mpro enzyme. The structure-based pharmacophore modeling was developed based on the co-crystallized structure of the enzyme with its biological active inhibitor. The generated hypotheses were applied for virtual screening based PhaseScore. Docking based virtual screening work-flow was used to generate hit compounds using HTVS, SP and XP based Glide GScore. The pharmacological and physicochemical properties of the best hit compounds were characterized using ADMET. Molecular dynamics simulations were performed to explore the binding affinities of the considered compounds. Binding studies revealed that compound ABBV-744 binds to the Mpro with strong affinity (Gbind -45.43 kcal/mol), and the complex is more stable in comparison with other protein-ligand complexes. Our study classified three best compounds which could be considered as promising inhibitors against main protease SARS-CoV-2 virus.

scholarly journals Inhibitor binding influences the protonation states of histidines in SARS-CoV-2 main protease

2020 ◽  
Author(s):  
Anna Pavlova ◽  
Diane L. Lynch ◽  
Isabella Daidone ◽  
Laura Zanetti-Polzi ◽  
Micholas Dean Smith ◽  
...  
Keyword(s):  
Drug Design ◽  
Bound States ◽  
Conformational Stability ◽  
Structure Based Drug Design ◽  
State Dependent ◽  
Main Protease ◽  
Highly Sensitive ◽  
Hydrogen Bond Networks ◽  
Dynamics Simulations ◽  
Catalytic Dyad

AbstractThe main protease (Mpro) of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is an attractive target for antiviral therapeutics. Recently, many high-resolution apo and inhibitor-bound structures of Mpro, a cysteine protease, have been determined, facilitating structure-based drug design. Mpro plays a central role in the viral life cycle by catalyzing the cleavage of SARS-CoV-2 polyproteins. In addition to the catalytic dyad His41-Cys145, Mpro contains multiple histidines including His163, His164, and His172. The protonation states of these histidines and the catalytic nu-cleophile Cys145 have been debated in previous studies of SARS-CoV Mpro, but have yet to be investigated for SARS-CoV-2. In this work we have used molecular dynamics simulations to determine the structural stability of SARS-CoV-2 Mpro as a function of the protonation assignments for these residues. We simulated both the apo and inhibitor-bound enzyme and found that the conformational stability of the binding site, bound inhibitors, and the hydrogen bond networks of Mpro are highly sensitive to these assignments. Additionally, the two inhibitors studied, the peptidomimetic N3 and an α-ketoamide, display distinct His41/His164 protonation-state-dependent stabilities. While the apo and the N3-bound systems favored Nδ (HD) and Nϵ (HE) protonation of His41 and His164, respectively, the α-ketoamide was not stably bound in this state. Our results illustrate the importance of using appropriate histidine protonation states to accurately model the structure and dynamics of SARS-CoV-2 Mpro in both the apo and inhibitor-bound states, a necessary prerequisite for drug-design efforts.

scholarly journals Novel Inhibitors of the Main Protease of SARS-CoV-2 Identified via a Molecular Dynamics Simulation-Guided in Vitro Assay

2020 ◽  
Author(s):  
Jennifer Loschwitz ◽  
Anna Jäckering ◽  
Monika Keutmann ◽  
Maryam Olagunju ◽  
Raphael J. Eberle ◽  
...  
Keyword(s):  
Molecular Dynamics ◽  
Binding Site ◽  
Drug Repurposing ◽  
Dynamics Simulation ◽  
Significant Activity ◽  
Vitro Assay ◽  
Protease Enzyme ◽  
Main Protease ◽  
Dynamics Simulations

<div>For the COVID-19 pandemic caused by SARS-CoV-2, there are currently no effective drugs or vaccines to treat this coronavirus infection. In this study, we focus on the main protease enzyme of SARS-CoV-2, 3CL pro , which is critical for viral replication. We employ explicit solvent molecular dynamics simulations of about 150 compounds docked into 3CL pro ’s binding site and that had emerged as good main protease ligands from our previous in silico screening of over 1.2 million compounds. By incoporating protein dynamics and applying a range of structural descriptors, such as the ability to form specific contacts with the catalytic dyad residues of 3CL pro and the structural fluctuations of the ligands in the binding site, we are able to further refine our compound selection. Fourteen compounds including estradiol shown to be the most promising based on our calculations were procured and screened against recombinant 3CL pro in a fluorescence assay. Eight of these compounds have significant activity in inhibiting the SARS-CoV-2 main protease. Among these are corilagin, a gallotannin, and lurasidone, an antipsychotic drug, which emerged as the most promising natural product and drug, respectively, and might thus be candidates for drug repurposing for the treatment of COVID-19. In addition, we also tested the inhibitory activity of testosterone, and our results reveal testosterone as possessing moderate inhibitory potency against the 3CL pro enzyme, which may thus provide an explanation why older men are more severely affected by COVID-19.</div>

scholarly journals Computational Prediction of Potential Inhibitors of the Main Protease of SARS-CoV-2

2020 ◽  
Vol 8 ◽  
Author(s):  
Renata Abel ◽  
María Paredes Ramos ◽  
Qiaofeng Chen ◽  
Horacio Pérez-Sánchez ◽  
Flaminia Coluzzi ◽  
...  
Keyword(s):  
Virtual Screening ◽  
Drug Repurposing ◽  
Computational Prediction ◽  
Pulmonary Diseases ◽  
Molecular Fingerprints ◽  
Computational Approaches ◽  
Main Protease ◽  
Dynamics Simulations ◽  
Potential Inhibitors ◽  
Clinical Potential

The rapidly developing pandemic, known as coronavirus disease 2019 (COVID-19) and caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has recently spread across 213 countries and territories. This pandemic is a dire public health threat—particularly for those suffering from hypertension, cardiovascular diseases, pulmonary diseases, or diabetes; without approved treatments, it is likely to persist or recur. To facilitate the rapid discovery of inhibitors with clinical potential, we have applied ligand- and structure-based computational approaches to develop a virtual screening methodology that allows us to predict potential inhibitors. In this work, virtual screening was performed against two natural products databases, Super Natural II and Traditional Chinese Medicine. Additionally, we have used an integrated drug repurposing approach to computationally identify potential inhibitors of the main protease of SARS-CoV-2 in databases of drugs (both approved and withdrawn). Roughly 360,000 compounds were screened using various molecular fingerprints and molecular docking methods; of these, 80 docked compounds were evaluated in detail, and the 12 best hits from four datasets were further inspected via molecular dynamics simulations. Finally, toxicity and cytochrome inhibition profiles were computationally analyzed for the selected candidate compounds.

scholarly journals Rutin Is a Low Micromolar Inhibitor of SARS-CoV-2 Main Protease 3CLpro: Implications for Drug Design of Quercetin Analogs

Biomedicines ◽  
2021 ◽  
Vol 9 (4) ◽  
pp. 375
Author(s):  
Bruno Rizzuti ◽  
Fedora Grande ◽  
Filomena Conforti ◽  
Ana Jimenez-Alesanco ◽  
Laura Ceballos-Laita ◽  
...  
Keyword(s):  
Drug Design ◽  
Simulation Techniques ◽  
Model Combining ◽  
Main Protease ◽  
Experimental Spectroscopy ◽  
Dynamics Simulations ◽  
Catalytic Dyad ◽  
Micromolar Range

The pandemic, due to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has stimulated the search for antivirals to tackle COVID-19 infection. Molecules with known pharmacokinetics and already approved for human use have been demonstrated or predicted to be suitable to be used either directly or as a base for a scaffold-based drug design. Among these substances, quercetin is known to be a potent in vitro inhibitor of 3CLpro, the SARS-CoV-2 main protease. However, its low in vivo bioavailability calls for modifications to its molecular structure. In this work, this issue is addressed by using rutin, a natural flavonoid that is the most common glycosylated conjugate of quercetin, as a model. Combining experimental (spectroscopy and calorimetry) and simulation techniques (docking and molecular dynamics simulations), we demonstrate that the sugar adduct does not hamper rutin binding to 3CLpro, and the conjugated compound preserves a high potency (inhibition constant in the low micromolar range, Ki = 11 μM). Although showing a disruption of the pseudo-symmetry in the chemical structure, a larger steric volume and molecular weight, and a higher solubility compared to quercetin, rutin is able to associate in the active site of 3CLpro, interacting with the catalytic dyad (His41/Cys145). The overall results have implications in the drug-design of quercetin analogs, and possibly other antivirals, to target the catalytic site of the SARS-CoV-2 3CLpro.

scholarly journals Novel Inhibitors of the Main Protease of SARS-CoV-2 Identified via a Molecular Dynamics Simulation-Guided in Vitro Assay

2020 ◽  
Author(s):  
Jennifer Loschwitz ◽  
Anna Jäckering ◽  
Monika Keutmann ◽  
Maryam Olagunju ◽  
Raphael J. Eberle ◽  
...  
Keyword(s):  
Molecular Dynamics ◽  
Binding Site ◽  
Drug Repurposing ◽  
Dynamics Simulation ◽  
Significant Activity ◽  
Vitro Assay ◽  
Protease Enzyme ◽  
Main Protease ◽  
Dynamics Simulations

<div>For the COVID-19 pandemic caused by SARS-CoV-2, there are currently no effective drugs or vaccines to treat this coronavirus infection. In this study, we focus on the main protease enzyme of SARS-CoV-2, 3CL pro , which is critical for viral replication. We employ explicit solvent molecular dynamics simulations of about 150 compounds docked into 3CL pro ’s binding site and that had emerged as good main protease ligands from our previous in silico screening of over 1.2 million compounds. By incoporating protein dynamics and applying a range of structural descriptors, such as the ability to form specific contacts with the catalytic dyad residues of 3CL pro and the structural fluctuations of the ligands in the binding site, we are able to further refine our compound selection. Fourteen compounds including estradiol shown to be the most promising based on our calculations were procured and screened against recombinant 3CL pro in a fluorescence assay. Eight of these compounds have significant activity in inhibiting the SARS-CoV-2 main protease. Among these are corilagin, a gallotannin, and lurasidone, an antipsychotic drug, which emerged as the most promising natural product and drug, respectively, and might thus be candidates for drug repurposing for the treatment of COVID-19. In addition, we also tested the inhibitory activity of testosterone, and our results reveal testosterone as possessing moderate inhibitory potency against the 3CL pro enzyme, which may thus provide an explanation why older men are more severely affected by COVID-19.</div>

Drug Repurposing Studies Targeting SARS-nCoV2: An Ensemble Docking Approach on Drug Target 3C-like Protease (3CLpro)

2020 ◽  
Author(s):  
Shruti Koulgi ◽  
Vinod Jani ◽  
Mallikarjunachari Uppuladinne ◽  
Uddhavesh Sonavane ◽  
Asheet Kumar Nath ◽  
...  
Keyword(s):  
Drug Repurposing ◽  
Drug Binding ◽  
Ensemble Docking ◽  
Drug Molecules ◽  
Drug Binding Site ◽  
Main Protease ◽  
Docking Approach ◽  
Novel Coronavirus ◽  
Markov State Modeling ◽  
Viral Polyprotein

<p>The COVID-19 pandemic has been responsible for several deaths worldwide. The causative agent behind this disease is the Severe Acute Respiratory Syndrome – novel Coronavirus 2 (SARS-nCoV2). SARS-nCoV2 belongs to the category of RNA viruses. The main protease, responsible for the cleavage of the viral polyprotein is considered as one of the hot targets for treating COVID-19. Earlier reports suggest the use of HIV anti-viral drugs for targeting the main protease of SARS-CoV, which caused SARS in the year 2002-03. Hence, drug repurposing approach may prove to be useful in targeting the main protease of SARS-nCoV2. The high-resolution crystal structure of 3CL<sup>pro</sup> (main protease) of SARS-nCoV2 (PDB ID: 6LU7) was used as the target. The Food and Drug Administration (FDA) approved and SWEETLEAD database of drug molecules were screened. The apo form of the main protease was simulated for a cumulative of 150 ns and 10 μs open source simulation data was used, to obtain conformations for ensemble docking. The representative structures for docking were selected using RMSD-based clustering and Markov State Modeling analysis. This ensemble docking approach for main protease helped in exploring the conformational variation in the drug binding site of the main protease leading to efficient binding of more relevant drug molecules. The drugs obtained as best hits from the ensemble docking possessed anti-bacterial and anti-viral properties. Small molecules with these properties may prove to be useful to treat symptoms exhibited in COVID-19. This <i>in-silico</i> ensemble docking approach would support identification of potential candidates for repurposing against COVID-19.</p>

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