scholarly journals Synthesis of Novel Halogenated Heterocyclic compounds and their uses as Target SARS-CoV-2 main Protease (Mpro) and Potential Anti-Covid-19

2021 ◽  
Author(s):  
Rafat Mohareb ◽  
Fahad M. Almutairi ◽  
Abdo A. Elfiky ◽  
Mahmoud A.A. Mahmoud ◽  
Wagnat W. Wardakhan ◽  
...  
Keyword(s):  
Molecular Dynamics ◽  
Active Site ◽  
Drug Target ◽  
Heterocyclic Compounds ◽  
Dynamics Simulation ◽  
Binding Modes ◽  
Main Protease ◽  
Target Molecules ◽  
Protein Active Site ◽  
Virtual Drug Screening

Abstract Since the first appearance of the coronavirus disease-2019 (COVID-19) in Wuhan, China, in December 2019, it has been spreading globally with devastating ramifications. The lack of anti-COVID-19 treatment to date warrants urgent research into potential therapeutic targets. Virtual drug screening techniques enable the identification of novel compounds that are capable of targeting the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) main protease (Mpro). The latter plays a fundamental role in mediating viral replication and transcription, rendering it an attractive drug target. In this study, twenty six novel halogenated, heterocyclic compounds, which can inhibit Mpro, were tested by molecular docking combined with molecular dynamics simulation. Three compounds showed the highest binding affinity to the protein active site and their binding modes coincide with that of Nelfinavir. The binding of the halogenated compounds to Mpro may inhibit the replication and transcription of SARS-CoV-2 and, ultimately, stop the virallife cycle. In times of dire need for anti-COVID-19 treatment, this study lays the groundwork for further experimental research to investigate the efficacy and potential medical uses of these compounds to treat COVID-19. Novel compounds including fused thiophene, pyrimidine and pyran derivatives were tested against human RNA N7-MTase (hRNMT) and selected viral N7-MTases such as SARS-CoV nsp14 and Vaccinia D1-D12 complex to evaluate their specificity and their molecular modeling was also studied in the aim of producing anti covid-19 target molecules.

scholarly journals Molecular Docking and Molecular Dynamics Studies of SARS-CoV-2 Inhibitors: Crocin, Digitoxigenin, Beta-Eudesmol and Favipiravir: Comparative Study

2021 ◽  
Vol 12 (4) ◽  
pp. 5591-5600
Keyword(s):  
Molecular Dynamics ◽  
Molecular Docking ◽  
Molecular Dynamics Simulation ◽  
Comparative Study ◽  
Active Site ◽  
Antiviral Treatment ◽  
Docking Study ◽  
The Other ◽  
Dynamics Simulation ◽  
Main Protease

In this study, Crocin, Digitoxigenin, Beta-Eudesmol, and Favipiravir were docked in the active site of SARS-CoV-2 main protease (PDB code: 6LU7). The docking study was followed by Molecular Dynamics simulation. The result indicates that Crocin and Digitoxigenin are the structures with the best affinity in the studied enzyme's binding site. Still, Molecular Dynamics simulation showed that Digitoxigenin is the molecule that fits better in the active site of the main protease. Therefore, this molecule could have a more potent antiviral treatment of COVID-19 than the other three studied compounds.

Prevention of SARS-CoV-2 Proliferation with a Novel and Potent Main Protease Inhibitor by Docking, ADMET, MM-PBSA, and Molecular Dynamics Simulation

2021 ◽  
pp. 2150014
Author(s):  
Akbar Noorbakhsh ◽  
Rafee Habib Askandar ◽  
Mohammad Shakib Alhagh ◽  
Chiako Farshadfar ◽  
Seyed Hamid Seyedi ◽  
...  
Keyword(s):  
Molecular Dynamics ◽  
Drug Target ◽  
Md Simulation ◽  
Vital Role ◽  
Lung Damage ◽  
Dynamics Simulation ◽  
Reference Drug ◽  
Main Protease ◽  
Poisson Boltzmann ◽  
Adme Properties

COVID-19 is the last disease caused by SARS-CoV-2 associated with a severe immune response and lung damage. The main protease (Mpro) has a vital role in SARS-CoV-2 proliferation. Moreover, humans lack homologous Mpro, which makes the Mpro a suitable drug target for the development of SARS-CoV-2 drugs. The purchasable L5000 library (Selleckchem Inc) includes 99,040 compounds that were used for virtual screening. After molecular docking and ADME studies, we selected a compound (WAY-604395) with a potent binding affinity to the Mpro active site and acceptable ADME properties compared to the reference drug (nelfinavir). Molecular dynamics (MD) simulation outcomes have proved that the Mpro-WAY604395 complex possesses a considerable value of flexibility, stability, compactness and binding energy. Our Molecular Mechanics Poisson–Boltzmann Surface Area (MM-PBSA) calculation demonstrates that WAY-604395 is more potent ([Formula: see text]272.19[Formula: see text]kcal mol[Formula: see text]) in comparison with nelfinavir ([Formula: see text]173.39[Formula: see text]kcal[Formula: see text]mol[Formula: see text]) against SARS-CoV-2 Mpro. In conclusion, we suggest that WAY-604395 has the potential for the treatment of SARS-CoV-2 by inhibition of the Mpro.

scholarly journals Drug Binding Dynamics of the Dimeric SARS-CoV-2 Main Protease, Determined by Molecular Dynamics Simulation

2020 ◽  
Author(s):  
Teruhisa S. KOMATSU ◽  
Noriaki Okimoto ◽  
Yohei M. KOYAMA ◽  
Yoshinori HIRANO ◽  
Gentaro MORIMOTO ◽  
...  
Keyword(s):  
Molecular Dynamics ◽  
Molecular Dynamics Simulation ◽  
Active Site ◽  
Binding Sites ◽  
Complex Structure ◽  
Drug Binding ◽  
Dynamics Simulation ◽  
Trajectory Data ◽  
Main Protease ◽  
Dynamic Sampling

<div> <div> <div> <p>We performed molecular dynamics simulation of the dimeric SARS-CoV-2 (severe acute respiratory syndrome corona virus 2) main protease (Mpro) to examine the binding dynamics of small molecular ligands. Seven HIV inhibitors, darunavir, indinavir, lopinavir, nelfinavir, ritonavir, saquinavir, and tipranavir, were used as the potential lead drugs to investigate access to the drug binding sites in Mpro. The frequently accessed sites on Mpro were classified based on contacts between the ligands and the protein, and the differences in site distributions of the encounter complex were observed among the ligands. All seven ligands showed binding to the active site at least twice in 28 simulations of 200 ns each. We further investigated the variations in the complex structure of the active site with the ligands, using microsecond order simulations. Results revealed a wide variation in the shapes of the binding sites and binding poses of the ligands. Additionally, the C-terminal region of the other chain often interacted with the ligands and the active site. Collectively, these findings indicate the importance of dynamic sampling of protein- ligand complexes and suggest the possibilities of further drug optimisations. <br></p><p><br></p><p><br> </p><div> <div> <div> <p>Raw trajectory data analysed in this paper and movie examples are available at the zenodo repository.<br></p> </div> </div> </div> </div> </div> </div>

scholarly journals Drug binding dynamics of the dimeric SARS-CoV-2 main protease, determined by molecular dynamics simulation

2020 ◽  
Vol 10 (1) ◽  
Author(s):  
Teruhisa S. Komatsu ◽  
Noriaki Okimoto ◽  
Yohei M. Koyama ◽  
Yoshinori Hirano ◽  
Gentaro Morimoto ◽  
...  
Keyword(s):  
Molecular Dynamics ◽  
Molecular Dynamics Simulation ◽  
Active Site ◽  
Binding Sites ◽  
Complex Structure ◽  
Drug Binding ◽  
Dynamics Simulation ◽  
Main Protease ◽  
Encounter Complex ◽  
Dynamic Sampling

Abstract We performed molecular dynamics simulation of the dimeric SARS-CoV-2 (severe acute respiratory syndrome corona virus 2) main protease (Mpro) to examine the binding dynamics of small molecular ligands. Seven HIV inhibitors, darunavir, indinavir, lopinavir, nelfinavir, ritonavir, saquinavir, and tipranavir, were used as the potential lead drugs to investigate access to the drug binding sites in Mpro. The frequently accessed sites on Mpro were classified based on contacts between the ligands and the protein, and the differences in site distributions of the encounter complex were observed among the ligands. All seven ligands showed binding to the active site at least twice in 28 simulations of 200 ns each. We further investigated the variations in the complex structure of the active site with the ligands, using microsecond order simulations. Results revealed a wide variation in the shapes of the binding sites and binding poses of the ligands. Additionally, the C-terminal region of the other chain often interacted with the ligands and the active site. Collectively, these findings indicate the importance of dynamic sampling of protein–ligand complexes and suggest the possibilities of further drug optimisations.

scholarly journals Drug Binding Dynamics of the Dimeric SARS-CoV-2 Main Protease, Determined by Molecular Dynamics Simulation

2020 ◽  
Author(s):  
Teruhisa S. KOMATSU ◽  
Noriaki Okimoto ◽  
Yohei M. KOYAMA ◽  
Yoshinori HIRANO ◽  
Gentaro MORIMOTO ◽  
...  
Keyword(s):  
Molecular Dynamics ◽  
Molecular Dynamics Simulation ◽  
Active Site ◽  
Binding Sites ◽  
Complex Structure ◽  
Drug Binding ◽  
Dynamics Simulation ◽  
Trajectory Data ◽  
Main Protease ◽  
Dynamic Sampling

<div> <div> <div> <p>We performed molecular dynamics simulation of the dimeric SARS-CoV-2 (severe acute respiratory syndrome corona virus 2) main protease (Mpro) to examine the binding dynamics of small molecular ligands. Seven HIV inhibitors, darunavir, indinavir, lopinavir, nelfinavir, ritonavir, saquinavir, and tipranavir, were used as the potential lead drugs to investigate access to the drug binding sites in Mpro. The frequently accessed sites on Mpro were classified based on contacts between the ligands and the protein, and the differences in site distributions of the encounter complex were observed among the ligands. All seven ligands showed binding to the active site at least twice in 28 simulations of 200 ns each. We further investigated the variations in the complex structure of the active site with the ligands, using microsecond order simulations. Results revealed a wide variation in the shapes of the binding sites and binding poses of the ligands. Additionally, the C-terminal region of the other chain often interacted with the ligands and the active site. Collectively, these findings indicate the importance of dynamic sampling of protein- ligand complexes and suggest the possibilities of further drug optimisations. <br></p><p><br></p><p><br> </p><div> <div> <div> <p>Raw trajectory data analysed in this paper and movie examples are available at the zenodo repository.<br></p> </div> </div> </div> </div> </div> </div>

scholarly journals Drug Binding Dynamics of the Dimeric SARS-CoV-2 Main Protease, Determined by Molecular Dynamics Simulation

2020 ◽  
Author(s):  
Teruhisa S. KOMATSU ◽  
Noriaki Okimoto ◽  
Yohei M. KOYAMA ◽  
Yoshinori HIRANO ◽  
Gentaro MORIMOTO ◽  
...  
Keyword(s):  
Molecular Dynamics ◽  
Molecular Dynamics Simulation ◽  
Active Site ◽  
Binding Sites ◽  
Complex Structure ◽  
Drug Binding ◽  
Dynamics Simulation ◽  
Trajectory Data ◽  
Main Protease ◽  
Dynamic Sampling

<div> <div> <div> <p>We performed molecular dynamics simulation of the dimeric SARS-CoV-2 (severe acute respiratory syndrome corona virus 2) main protease (Mpro) to examine the binding dynamics of small molecular ligands. Seven HIV inhibitors, darunavir, indinavir, lopinavir, nelfinavir, ritonavir, saquinavir, and tipranavir, were used as the potential lead drugs to investigate access to the drug binding sites in Mpro. The frequently accessed sites on Mpro were classified based on contacts between the ligands and the protein, and the differences in site distributions of the encounter complex were observed among the ligands. All seven ligands showed binding to the active site at least twice in 28 simulations of 200 ns each. We further investigated the variations in the complex structure of the active site with the ligands, using microsecond order simulations. Results revealed a wide variation in the shapes of the binding sites and binding poses of the ligands. Additionally, the C-terminal region of the other chain often interacted with the ligands and the active site. Collectively, these findings indicate the importance of dynamic sampling of protein- ligand complexes and suggest the possibilities of further drug optimisations. <br></p><p><br></p><p><br> </p><div> <div> <div> <p>Raw trajectory data analysed in this paper and movie examples are available at the zenodo repository.<br></p> </div> </div> </div> </div> </div> </div>

scholarly journals Computational Investigations on the Binding Mode of Ligands for the Cannabinoid-Activated G Protein-Coupled Receptor GPR18

Biomolecules ◽  
2020 ◽  
Vol 10 (5) ◽  
pp. 686 ◽  
Author(s):  
Alexander Neumann ◽  
Viktor Engel ◽  
Andhika B. Mahardhika ◽  
Clara T. Schoeder ◽  
Vigneshwaran Namasivayam ◽  
...  
Keyword(s):  
Molecular Dynamics ◽  
Molecular Dynamics Simulation ◽  
G Protein ◽  
Phenyl Ring ◽  
Binding Mode ◽  
Dynamics Simulation ◽  
Simulation Studies ◽  
Binding Modes ◽  
G Protein Coupled Receptor ◽  
G Protein Coupled

GPR18 is an orphan G protein-coupled receptor (GPCR) expressed in cells of the immune system. It is activated by the cannabinoid receptor (CB) agonist ∆9-tetrahydrocannabinol (THC). Several further lipids have been proposed to act as GPR18 agonists, but these results still require unambiguous confirmation. In the present study, we constructed a homology model of the human GPR18 based on an ensemble of three GPCR crystal structures to investigate the binding modes of the agonist THC and the recently reported antagonists which feature an imidazothiazinone core to which a (substituted) phenyl ring is connected via a lipophilic linker. Docking and molecular dynamics simulation studies were performed. As a result, a hydrophobic binding pocket is predicted to accommodate the imidazothiazinone core, while the terminal phenyl ring projects towards an aromatic pocket. Hydrophobic interaction of Cys251 with substituents on the phenyl ring could explain the high potency of the most potent derivatives. Molecular dynamics simulation studies suggest that the binding of imidazothiazinone antagonists stabilizes transmembrane regions TM1, TM6 and TM7 of the receptor through a salt bridge between Asp118 and Lys133. The agonist THC is presumed to bind differently to GPR18 than to the distantly related CB receptors. This study provides insights into the binding mode of GPR18 agonists and antagonists which will facilitate future drug design for this promising potential drug target.

scholarly journals Identification of Anti-SARS-CoV-2 Compounds from Food Using QSAR-Based Virtual Screening, Molecular Docking, and Molecular Dynamics Simulation Analysis

2021 ◽  
Vol 14 (4) ◽  
pp. 357
Author(s):  
Magdi E. A. Zaki ◽  
Sami A. Al-Hussain ◽  
Vijay H. Masand ◽  
Siddhartha Akasapu ◽  
Sumit O. Bajaj ◽  
...  
Keyword(s):  
Molecular Dynamics ◽  
Molecular Docking ◽  
Virtual Screening ◽  
Simulation Analysis ◽  
Qsar Model ◽  
Quantitative Structure Activity Relationship ◽  
Dynamics Simulation ◽  
Multilinear Regression ◽  
Qsar Analysis ◽  
Main Protease

Due to the genetic similarity between SARS-CoV-2 and SARS-CoV, the present work endeavored to derive a balanced Quantitative Structure−Activity Relationship (QSAR) model, molecular docking, and molecular dynamics (MD) simulation studies to identify novel molecules having inhibitory potential against the main protease (Mpro) of SARS-CoV-2. The QSAR analysis developed on multivariate GA–MLR (Genetic Algorithm–Multilinear Regression) model with acceptable statistical performance (R2 = 0.898, Q2loo = 0.859, etc.). QSAR analysis attributed the good correlation with different types of atoms like non-ring Carbons and Nitrogens, amide Nitrogen, sp2-hybridized Carbons, etc. Thus, the QSAR model has a good balance of qualitative and quantitative requirements (balanced QSAR model) and satisfies the Organisation for Economic Co-operation and Development (OECD) guidelines. After that, a QSAR-based virtual screening of 26,467 food compounds and 360 heterocyclic variants of molecule 1 (benzotriazole–indole hybrid molecule) helped to identify promising hits. Furthermore, the molecular docking and molecular dynamics (MD) simulations of Mpro with molecule 1 recognized the structural motifs with significant stability. Molecular docking and QSAR provided consensus and complementary results. The validated analyses are capable of optimizing a drug/lead candidate for better inhibitory activity against the main protease of SARS-CoV-2.

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