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 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 Repurposing of FDA Approved Drugs for the Identification of Potential Inhibitors of SARS-CoV-2 Main Protease

2020 ◽  
Author(s):  
Abhik Kumar Ray ◽  
Parth Sarthi Sen Gupta ◽  
Saroj Kumar Panda ◽  
Satyaranjan Biswal ◽  
Malay Kumar Rana
Keyword(s):  
Virtual Screening ◽  
Binding Energies ◽  
Great Promise ◽  
Main Protease ◽  
Promising Target ◽  
Inhibitory Potential ◽  
Novel Coronavirus ◽  
Approved Drugs ◽  
Potential Inhibitors ◽  
Fda Approved Drugs

<p>COVID-19, responsible for several deaths, demands a cumulative effort of scientists worldwide to curb the pandemic. The main protease, responsible for the cleavage of the polyprotein and formation of replication complex in virus, is considered as a promising target for the development of potential inhibitors to treat the novel coronavirus. The effectiveness of FDA approved drugs targeting the main protease in previous SARS-COV (s) reported earlier indicates the chances of success for the repurposing of FDA drugs against SARS-COV-2. Therefore, in this study, molecular docking and virtual screening of FDA approved drugs, primarily of three categories: antiviral, antimalarial, and peptide, are carried out to investigate their inhibitory potential against the main protease. Virtual screening has identified 53 FDA drugs on the basis of their binding energies (< -7.0 kcal/mol), out of which the top two drugs Velpatasvir (-9.1 kcal/mol) and Glecaprevir (-9.0 kcal/mol) seem to have great promise. These drugs have a stronger affinity to the SARS-CoV-2 main protease than the crystal bound inhibitor α-ketoamide 13B (-6.7 kcal/mol) or Indinavir (-7.5 kcal/mol) that has been proposed in a recent study as one of the best drugs for SARS-CoV-2. The <i>in-silico</i> efficacies of the screened drugs could be instructive for further biochemical and structural investigation for repurposing. The molecular dynamics studies on the shortlisted drugs are underway. </p>

scholarly journals N,N’-Dialkyl-2-Thiobarbituric acid based Sulfonamides as potential SARS-CoV-2 main protease inhibitors

2021 ◽  
Author(s):  
Muhammad Sarfraz ◽  
Abdul Rauf ◽  
Paul A Keller ◽  
Ashfaq Mahmood Qureshi
Keyword(s):  
Protease Inhibitors ◽  
In Silico ◽  
Thiobarbituric Acid ◽  
Binding Energies ◽  
Ligand Efficiency ◽  
Lead Compounds ◽  
Protease Enzyme ◽  
Main Protease ◽  
Docking Energy ◽  
Better Than

An efficient methodology was developed to avail novel N,N’-dialkyl-2-thiobarbituric acid based sulfonamides S1-S4 in good to excellent yields (84-95%). The synthesized compounds S1-S4 were docked to screen their In-silico activities against two enzymes i.e. SARS-CoV-2 main protease enzyme with unliganded active site (2019-nCoV, coronavirus disease 2019, COVID-19) PDB ID: 6Y84 and SARS-CoV-2 Mpro PDB ID: 6LU7. Furthermore, some In-silico physicochemical and physicokinetic properties were evaluated using OSIRIS property explorer online, molinspiration property calculator, ADMET property calculator and GUSAR to assess these compounds as potential candidates as lead compounds for the quest of SARS- CoV-2 main protease inhibitors. Molecular docking analyses of the synthesized compounds predicted that compound S3 is more potent as SARS-CoV-2 main protease inhibitor with binding energy -11.65 Kcal/mol in comparison to reference inhibitor N3 (-10.95 Kcal/mol), whereas, compounds S1, S2 and S4 recorded comparable binding energies -9.89 Kcal/mol, -10.84 Kcal/mol and -10.94 Kcal/mol with reference inhibitor N3, however much better than remdesivir (-9.85 Kcal/mol). In case of SARS-CoV-2 Mpro, all compounds S1-S4 with docking energy values as -7.28, -8.38, -8.31 and -7.34 Kcal/mol were found potent in comparison to reference inhibitor N3 (-6.31 Kcal/mol) as well as remdesivir (-6.33 Kcal/mol). Ligand efficiency values against the target SARS-CoV-2 proteins as well as α-glucosidase and DNA-(apurinic or apyrimidinic site) lyase inhibition results of these newly synthesized compounds were also found promising.

scholarly journals Natural xanthone compounds as promising drug candidates against COVID-19 - An integrated molecular docking and dynamics simulation study

2020 ◽  
Author(s):  
Shravan Kumar Gunda ◽  
Hima Kumari P ◽  
Gourav Choudhir ◽  
Anuj Kumar ◽  
P B. Kavi Kishor ◽  
...  
Keyword(s):  
Molecular Docking ◽  
Antiviral Agents ◽  
Binding Energies ◽  
Dynamics Simulation ◽  
Lipinski’S Rule ◽  
Drug Candidates ◽  
Main Protease ◽  
Lipinski’S Rule Of Five ◽  
Dynamics Simulations ◽  
Potential Inhibitors

Abstract Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) causes coronavirus disease2019 (COVID-19). SARS-CoV-2 is known for its high pathogenicity and transmission due to thepresence of polybasic cleavage sites. No specific drug is available for the treatment. To identifythe potential inhibitors, we have performed molecular docking against the SARS-CoV-2 mainprotease (6Y84) with fifteen important natural xanthone compounds. The docking results showedall the compounds exhibited good binding energies and interactions with the main protease. Thevalidation of representative docking complexes through molecular dynamics simulations showedthat xanthones binds with a higher binding affinity and lower free energy than the standardligand with Brasixanthone C and Brasixanthone B on 50 ns. Natural xanthone compounds havealso passed the Absorption, Distribution, Metabolism, and Excretion (ADME) property criteriaas well as Lipinski’s rule of five. The present integrated molecular docking and dynamicssimulations study unveil the use of xanthones as potential antiviral agents against SARS-CoV-2.

scholarly journals In silico discovery of SARS-CoV-2 main protease inhibitors from the carboline and quinoline database

2021 ◽  
Author(s):  
Eldar Muhtar ◽  
Mengyang Wang ◽  
Haimei Zhu
Keyword(s):  
Molecular Dynamics ◽  
Molecular Mechanics ◽  
Protease Inhibitors ◽  
Surface Area ◽  
In Silico ◽  
Binding Energies ◽  
Main Protease ◽  
Poisson Boltzmann ◽  
Dynamics Simulations ◽  
Potential Inhibitors

Aim: SARS-CoV-2 caused more than 3.8 million deaths according to the WHO. In this urgent circumstance, we aimed at screening out potential inhibitors targeting the main protease of SARS-CoV-2. Materials & methods: An in-house carboline and quinoline database including carboline, quinoline and their derivatives was established. A virtual screening in carboline and quinoline database, 50 ns molecular dynamics simulations and molecular mechanics Poisson−Boltzmann surface area calculations were carried out. Results: The top 12 molecules were screened out preliminarily. The molecular mechanics Poisson−Boltzmann surface area ranking showed that p59_7m, p12_7e, p59_7k stood out with the lowest binding energies of -24.20, -17.98, -17.67 kcal/mol, respectively. Conclusion: The study provides powerful in silico results that indicate the selected molecules are valuable for further evaluation as SARS-CoV-2 main protease inhibitors.

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 Repurposing of FDA Approved Drugs for the Identification of Potential Inhibitors of SARS-CoV-2 Main Protease

2020 ◽  
Author(s):  
Abhik Kumar Ray ◽  
Parth Sarthi Sen Gupta ◽  
Saroj Kumar Panda ◽  
Satyaranjan Biswal ◽  
Malay Kumar Rana
Keyword(s):  
Virtual Screening ◽  
Binding Energies ◽  
Great Promise ◽  
Main Protease ◽  
Promising Target ◽  
Inhibitory Potential ◽  
Novel Coronavirus ◽  
Approved Drugs ◽  
Potential Inhibitors ◽  
Fda Approved Drugs

<p>COVID-19, responsible for several deaths, demands a cumulative effort of scientists worldwide to curb the pandemic. The main protease, responsible for the cleavage of the polyprotein and formation of replication complex in virus, is considered as a promising target for the development of potential inhibitors to treat the novel coronavirus. The effectiveness of FDA approved drugs targeting the main protease in previous SARS-COV (s) reported earlier indicates the chances of success for the repurposing of FDA drugs against SARS-COV-2. Therefore, in this study, molecular docking and virtual screening of FDA approved drugs, primarily of three categories: antiviral, antimalarial, and peptide, are carried out to investigate their inhibitory potential against the main protease. Virtual screening has identified 53 FDA drugs on the basis of their binding energies (< -7.0 kcal/mol), out of which the top two drugs Velpatasvir (-9.1 kcal/mol) and Glecaprevir (-9.0 kcal/mol) seem to have great promise. These drugs have a stronger affinity to the SARS-CoV-2 main protease than the crystal bound inhibitor α-ketoamide 13B (-6.7 kcal/mol) or Indinavir (-7.5 kcal/mol) that has been proposed in a recent study as one of the best drugs for SARS-CoV-2. The <i>in-silico</i> efficacies of the screened drugs could be instructive for further biochemical and structural investigation for repurposing. The molecular dynamics studies on the shortlisted drugs are underway. </p>

scholarly journals Screening of Clinically Approved and Investigation Drugs as Potential Inhibitors of COVID-19 Main Protease: A Virtual Drug Repurposing Study

2020 ◽  
Author(s):  
Serdar Durdagi ◽  
Busecan Aksoydan ◽  
Berna Dogan ◽  
Kader Sahin ◽  
Aida Shahraki
Keyword(s):  
Virtual Screening ◽  
Clinical Investigation ◽  
Drug Repurposing ◽  
Md Simulations ◽  
Binding Energies ◽  
New Drugs ◽  
Docking Simulations ◽  
New Drug ◽  
Main Protease ◽  
Glide Docking

<div>There is an urgent need for a new drug against COVID-19. Since designing a new drug and testing its pharmacokinetics and pharmacodynamics properties may take years, here we used a physics-driven high throughput virtual screening drug re-purposing approach to identify new compounds against COVID-19. As the molecules considered in repurposing studies passed through several stages and have well-defined profiles, they would not require prolonged preclinical studies and hence, they would be excellent candidates in the cases of disease emergencies or outbreaks. While the spike protein is the key for the virus to enter the cell though the interaction with ACE2, enzymes such as main protease are crucial for the life cycle of the virus. This protein is one of the most attractive targets for the development of new drugs against</div><div>COVID-19 due to its pivotal role in the replication and transcription of the virus. We used 7922 FDA approved small molecule drugs as well as compounds in clinical investigation from NIH Chemical Genomics Center (NCGC) Pharmaceutical Collection (NPC) database in our drug repurposing study. Both apo and holo forms of target protein COVID-19 main proteases were used in virtual screening. Target proteins were retrieved from protein data bank (PDB IDs, 6M03 and 6LU7). Standard Precision (SP) protocol of Glide docking program of Maestro was used in docking. Compounds were then ranked based on their docking scores that represents binding energies. Top-30 compounds from each docking simulations were considered initially in short (10-ns) molecular dynamics (MD) simulations and their average binding energies using collected 1000 trajectories throughout the MD simulations were calculated by Molecular Mechanics Generalized Born Surface Area (MM/GBSA) method. Selected promising hit compounds based on average MM/GBSA scores were then used in long (100-ns) MD simulations. These numerical calculations showed that the following 6 compounds can be considered as COVID-19 Main Protease inhibitors: Lasinavir, Brecanavir, Telinavir, Rotigaptide, 1,3-Bis-(2-ethoxycarbonylchromon-5-yloxy)-2-(lysyloxy)propane and Pimelautide.</div>

scholarly journals Computer-aided approaches reveal trihydroxychroman and pyrazolone derivatives as potential inhibitors of SARS-CoV-2 virus main protease

2021 ◽  
Vol 71 (3) ◽  
pp. 325-333
Author(s):  
Noor Atatreh ◽  
Shaima Hasan ◽  
Bassam R. Ali ◽  
Mohammad A. Ghattas
Keyword(s):  
Protein Complexes ◽  
Binding Energies ◽  
World Health ◽  
Binding Modes ◽  
Dynamic Simulations ◽  
Protease Enzyme ◽  
Main Protease ◽  
Pyrazolone Derivatives ◽  
Starting Point ◽  
Potential Inhibitors

AbstractCOVID-19 was declared a pandemic by the World Health Organization (WHO) in March 2020. The disease is caused by severe acute respiratory syndrome coronavirus 2 (SARSCoV-2). The aim of this study is to target the SARS-CoV-2 virus main protease (Mpro) via structure-based virtual screening. Consequently, > 580,000 ligands were processed via several filtration and docking steps, then the top 21 compounds were analysed extensively via MM-GBSA scoring and molecular dynamic simulations. Interestingly, the top compounds showed favorable binding energies and binding patterns to the protease enzyme, forming interactions with several key residues. Trihydroxychroman and pyrazolone derivatives, SN02 and SN18 ligands, exhibited very promising binding modes along with the best MM-GBSA scoring of –40.9 and –41.2 kcal mol−1, resp. MD simulations of 300 ns for the ligand-protein complexes of SN02 and SN18 affirmed the previously attained results of the potential inhibition activity of these two ligands. These potential inhibitors can be the starting point for further studies to pave way for the discovery of new antiviral drugs for SARS-CoV-2.

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