scholarly journals Discovery of Natural Phenol Catechin as a Multitargeted Agent Against SARS-CoV-2 For the Plausible Therapy of COVID-19

2020 ◽  
Author(s):  
Chandra Bhushan Mishra ◽  
Preeti Pandey ◽  
Ravi Datta Sharma ◽  
Raj Kumar Mongre ◽  
Andrew M Lynn ◽  
...  
Keyword(s):  
Free Energy ◽  
Molecular Interactions ◽  
Nucleocapsid Protein ◽  
Rational Design ◽  
Hydrophobic Interactions ◽  
Binding Free Energy ◽  
Nonstructural Protein ◽  
Cathepsin L ◽  
Target Proteins ◽  
Drug Molecules

The global pandemic crisis, COVID-19 caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has claimed the lives of millions of people across the world. Development and testing of anti-SARS-CoV-2 drugs or vaccines, are not turned to be realistic in the timeframe needed to combat this pandemic. Thus, rigorous efforts are still ongoing for the drug repurposing as a clinical treatment strategy to control COVID-19. Here we report a comprehensive computational approach to identify the multi-targeted drug molecules against the SARS-CoV-2 proteins, which are crucially involved in the viral-host interaction, replication of the virus inside the host, disease progression and transmission of coronavirus infection. Virtual screening of 72 FDA approved potential antiviral drugs against the target proteins: Spike (S) glycoprotein, human angiotensin-converting enzyme 2 (hACE2), 3-chymotrypsin-like cysteine protease (3CLpro), Cathepsin L, Nucleocapsid protein, RNA-dependent RNA polymerase (RdRp) and nonstructural protein 6 (NSP6) resulted in the selection of seven drugs which preferentially binds to the target proteins. Further, the molecular interactions determined by MD simulation, free energy landscape and the binding free energy estimation, using MM-PBSA revealed that among 72 drug molecules, catechin (flavan-3-ol) can effectively bind to 3CLpro, Cathepsin L, RBD of S protein, NSP-6, and Nucleocapsid protein. It is more conveniently involved in key molecular interactions, showing binding free energy (ΔGbind) in the range of -5.09 kcal/mol (Cathepsin L) to -26.09 kcal/mol (NSP6). At the binding pocket, catechin is majorly stabilized by the hydrophobic interactions, displays ΔEvdW values -7.59 to -37.39 kcal/mol. Thus, the structural insights of better binding affinity and favourable molecular interaction of catechin towards multiple target proteins, signifies that catechin can be potentially explored as a multitargeted agent in the rational design of effective therapies against COVID-19.<br>

scholarly journals Discovery of Natural Phenol Catechin as a Multitargeted Agent Against SARS-CoV-2 For the Plausible Therapy of COVID-19

2020 ◽  
Author(s):  
Chandra Bhushan Mishra ◽  
Preeti Pandey ◽  
Ravi Datta Sharma ◽  
Raj Kumar Mongre ◽  
Andrew M Lynn ◽  
...  
Keyword(s):  
Free Energy ◽  
Molecular Interactions ◽  
Nucleocapsid Protein ◽  
Rational Design ◽  
Hydrophobic Interactions ◽  
Binding Free Energy ◽  
Nonstructural Protein ◽  
Cathepsin L ◽  
Target Proteins ◽  
Drug Molecules

The global pandemic crisis, COVID-19 caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has claimed the lives of millions of people across the world. Development and testing of anti-SARS-CoV-2 drugs or vaccines, are not turned to be realistic in the timeframe needed to combat this pandemic. Thus, rigorous efforts are still ongoing for the drug repurposing as a clinical treatment strategy to control COVID-19. Here we report a comprehensive computational approach to identify the multi-targeted drug molecules against the SARS-CoV-2 proteins, which are crucially involved in the viral-host interaction, replication of the virus inside the host, disease progression and transmission of coronavirus infection. Virtual screening of 72 FDA approved potential antiviral drugs against the target proteins: Spike (S) glycoprotein, human angiotensin-converting enzyme 2 (hACE2), 3-chymotrypsin-like cysteine protease (3CLpro), Cathepsin L, Nucleocapsid protein, RNA-dependent RNA polymerase (RdRp) and nonstructural protein 6 (NSP6) resulted in the selection of seven drugs which preferentially binds to the target proteins. Further, the molecular interactions determined by MD simulation, free energy landscape and the binding free energy estimation, using MM-PBSA revealed that among 72 drug molecules, catechin (flavan-3-ol) can effectively bind to 3CLpro, Cathepsin L, RBD of S protein, NSP-6, and Nucleocapsid protein. It is more conveniently involved in key molecular interactions, showing binding free energy (ΔGbind) in the range of -5.09 kcal/mol (Cathepsin L) to -26.09 kcal/mol (NSP6). At the binding pocket, catechin is majorly stabilized by the hydrophobic interactions, displays ΔEvdW values -7.59 to -37.39 kcal/mol. Thus, the structural insights of better binding affinity and favourable molecular interaction of catechin towards multiple target proteins, signifies that catechin can be potentially explored as a multitargeted agent in the rational design of effective therapies against COVID-19.<br>

scholarly journals Identifying the natural polyphenol catechin as a multi-targeted agent against SARS-CoV-2 for the plausible therapy of COVID-19: an integrated computational approach

2020 ◽  
Author(s):  
Chandra Bhushan Mishra ◽  
Preeti Pandey ◽  
Ravi Datta Sharma ◽  
Md Zubbair Malik ◽  
Raj Kumar Mongre ◽  
...  
Keyword(s):  
Molecular Interactions ◽  
Nucleocapsid Protein ◽  
Hydrophobic Interactions ◽  
Binding Free Energy ◽  
Computational Approach ◽  
Dynamics Simulation ◽  
Structural Protein ◽  
Target Proteins ◽  
Drug Molecules ◽  
Targeted Agent

Abstract The global pandemic crisis, coronavirus disease 2019 (COVID-19), caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has claimed the lives of millions of people across the world. Development and testing of anti-SARS-CoV-2 drugs or vaccines have not turned to be realistic within the timeframe needed to combat this pandemic. Here, we report a comprehensive computational approach to identify the multi-targeted drug molecules against the SARS-CoV-2 proteins, whichare crucially involved in the viral–host interaction, replication of the virus inside the host, disease progression and transmission of coronavirus infection. Virtual screening of 75 FDA-approved potential antiviral drugs against the target proteins, spike (S) glycoprotein, human angiotensin-converting enzyme 2 (hACE2), 3-chymotrypsin-like cysteine protease (3CLpro), cathepsin L (CTSL), nucleocapsid protein, RNA-dependent RNA polymerase (RdRp) and non-structural protein 6 (NSP6), resulted in the selection of seven drugs which preferentially bind to the target proteins. Further, the molecular interactions determined by molecular dynamics simulation revealed that among the 75 drug molecules, catechin can effectively bind to 3CLpro, CTSL, RBD of S protein, NSP6 and nucleocapsid protein. It is more conveniently involved in key molecular interactions, showing binding free energy (ΔGbind) in the range of −5.09 kcal/mol (CTSL) to −26.09 kcal/mol (NSP6). At the binding pocket, catechin is majorly stabilized by the hydrophobic interactions, displays ΔEvdW values: −7.59 to −37.39 kcal/mol. Thus, the structural insights of better binding affinity and favorable molecular interaction of catechin toward multiple target proteins signify that catechin can be potentially explored as a multi-targeted agent against COVID-19.

scholarly journals Molecular modeling study on the drug resistance mechanism of NS5B polymerase to TMC647055

2016 ◽  
Vol 94 (2) ◽  
pp. 147-158 ◽  
Author(s):  
Huiqun Wang ◽  
Wei Cui ◽  
Chenchen Guo ◽  
Bo-Zhen Chen ◽  
Mingjuan Ji
Keyword(s):  
Drug Resistance ◽  
Free Energy ◽  
Rational Design ◽  
Binding Free Energy ◽  
Resistance Mechanism ◽  
Free Energy Calculations ◽  
Side Chain ◽  
Free Energy Decomposition ◽  
Hcv Ns5b ◽  
Ns5b Polymerase

NS5B polymerase plays an important role in viral replication machinery. TMC647055 (TMC) is a novel and potent non-nucleoside inhibitor of the HCV NS5B polymerase. However, mutations that result in drug resistance to TMC have been reported. In this study, we used molecular dynamics (MD) simulations, binding free energy calculations, and free energy decomposition to investigate the drug resistance mechanism of HCV to TMC resulting from L392I, P495T, P495S, and P495L mutations in NS5B polymerase. From the calculated results we determined that the decrease in the binding affinity between TMC and NS5BL392I polymerase is mainly caused by the extra methyl group at the CB atom of Ile. The polarity of the side-chain of residue 495 has no distinct influence on residue 495 binding with TMC, whereas the smaller size of the side-chain of residue 495 causes a substantial decrease in the van der Walls interaction between TMC and residue 495. Moreover, the longer length of the side-chain of residue 495 has a significant effect on the electrostatic interaction between TMC and Arg-503. Finally, we performed the same calculations and detailed analysis on other 3 mutations (L392V, P495V, and P495I). The results further confirmed our conclusions. The computational results not only reveal the drug resistance mechanism between TMC647055 and NS5B polymerase, but also provide valuable information for the rational design of more potent non-nucleoside inhibitors targeting HCV NS5B polymerase.

scholarly journals Structure-Based Virtual Screening and Molecular Dynamic Simulation Studies to Identify Novel Cytochrome bc1 Inhibitors as Antimalarial Agents

2013 ◽  
Vol 2013 ◽  
pp. 1-9 ◽  
Author(s):  
Rahul P. Gangwal ◽  
Gaurao V. Dhoke ◽  
Mangesh V. Damre ◽  
Kanchan Khandelwal ◽  
Abhay T. Sangamwar
Keyword(s):  
Free Energy ◽  
Molecular Docking ◽  
Molecular Dynamic Simulation ◽  
Molecular Dynamic ◽  
Dynamic Simulation ◽  
Hydrophobic Interactions ◽  
Binding Free Energy ◽  
Van Der Waals Interactions ◽  
Electrostatic Energy ◽  
Hydrogen Bond Acceptor

Cytochrome bc1 (EC 1.10.2.2, bc1) is an essential component of the cellular respiratory chain, which catalyzes electron transfer from quinol to cytochrome c and concomitantly the translocation of protons across the membrane. It has been identified as a promising target in malaria parasites. The structure-based pharmacophore modelling and molecular dynamic simulation approach have been employed to identify novel inhibitors of cytochrome bc1. The best structure-based pharmacophore hypothesis (Hypo1) consists of one hydrogen bond acceptor (HBA), one general hydrophobic (HY), and two hydrophobic aromatic features (HYAr). Further, hydrogen interactions and hydrophobic interactions of known potent inhibitors with cytochrome bc1 were compared with Hypo1, which showed that the Hypo1 has good predictive ability. The validated Hypo1 was used to screen the chemical databases. The hits obtained were subsequently subjected to the molecular docking analysis to identify false-positive hits. Moreover, the molecular docking results were further validated by molecular dynamics simulations. Binding-free energy analysis using MM-GBSA method reveals that the van der Waals interactions and the electrostatic energy provide the basis for favorable absolute free energy of the complex. The five virtual hits were identified as possible candidates for the designing of potent cytochrome bc1 inhibitors.

scholarly journals Virtual Screening and Free Energy Estimation for Identifying Mycobacterium Tuberculosis Flavoenzyme DprE1 Inhibitors

2020 ◽  
Author(s):  
Niranjan Kumar ◽  
Rakesh Srivastava ◽  
Amresh Prakash ◽  
Andrew M Lynn
Keyword(s):  
Free Energy ◽  
Mycobacterium Tuberculosis ◽  
Virtual Screening ◽  
Binding Free Energy ◽  
Md Simulations ◽  
Energy Estimation ◽  
Chemical Libraries ◽  
Drug Molecules ◽  
Rational Drug ◽  
Drug Designing

<p>we investigated the promising MTB drug target protein, DprE1 (decaprenylphosphoryl-β-d-ribose 2’-epimerase), involve in cell was synthesis of Mycobacterium tuberculosis and plays a crucial role<b> </b>in host pathogenesis, virulence, lethality and survival under stress. Considering the emergence of different variants of drug resistant MTB are one of the major threats worldwide which essentially requires more effective new drug molecules with no major side effects. Here, we employed comprehensive computational methods for the structure based virtual screening of bioactive anti-tuberculosis compounds from chemical libraries ChEMBL, characterized the physicochemical properties analyses and the trajectories obtained from MD simulations were used for estimation of binding free energy, applying molecular theory of solvation (MM/PBSA, MM/GBSA AND MM/3DRISM-KH). All results were compared with known DprE1 inhibitors. Our studies suggest that four compounds (ChEMBL2441313, ChEMBL2338605, ChEMBL441373 and ChEMBL1607606) compounds may be explored as lead molecules for the rational drug designing of DprE1-inhibitors in MTB therapy.</p><br>

scholarly journals Binding mechanism of SARS-CoV-2 spike protein with human ACE2 receptor

2020 ◽  
Author(s):  
Rajendra P Koirala ◽  
Bidhya Thapa ◽  
Shyam P Khanal ◽  
Jhulan Powrel ◽  
Rajendra P Adhikari ◽  
...  
Keyword(s):  
Free Energy ◽  
Contact Surface ◽  
Hydrophobic Interactions ◽  
Binding Free Energy ◽  
Umbrella Sampling ◽  
Spike Protein ◽  
Receptor Protein ◽  
Virus Protein ◽  
Binding Mechanism ◽  
Binding Interface

Abstract SARS-CoV-2 virus interacts via C-terminal domain of spike protein to human cell receptor protein hACE2. Amino acid residues residing at the interface play vital role in binding of SARS-CoV-2 CTD to hACE2. The detailed atomic level inves- tigation of interactions at binding interface of SARS-CoV-2 CTD/hACE2 provides indispensable information on better understanding of location for drug target. In the present work, we have studied the dynamical behaviour of the complex by ana- lyzing the molecular dynamics (MD) trajectories. The major interacting residues of SARS-CoV-2 CTD and hACE2 have been identified by analyzing the non-bonded interactions such as hydrogen bondings, salt bridges, hydrophobic interactions, van der Waals interactions etc. Umbrella sampling method has been used to estimate the binding free energy for in-depth understanding of binding mechanism between virus protein and host receptor. The binding free energy difference, key residues at the interface, important atomic interactions and contact surface areas have been compared with the molecular complex of SARS-CoV and hACE2. Relatively larger contact surface area, more non-bonded interactions as well as greater binding free energy provide the evidence for favorable binding of SARS-CoV-2 with hACE2 receptor than SARS-CoV.

scholarly journals Ligand binding to telomeric G-quadruplex DNA investigated by funnel-metadynamics simulations

2017 ◽  
Vol 114 (11) ◽  
pp. E2136-E2145 ◽  
Author(s):  
Federica Moraca ◽  
Jussara Amato ◽  
Francesco Ortuso ◽  
Anna Artese ◽  
Bruno Pagano ◽  
...  
Keyword(s):  
Free Energy ◽  
Ligand Binding ◽  
Rational Design ◽  
Binding Free Energy ◽  
Binding Mode ◽  
Dna Interaction ◽  
Accurate Estimate ◽  
Binding Modes ◽  
Binding Mechanism ◽  
Promoter Regions

G-quadruplexes (G4s) are higher-order DNA structures typically present at promoter regions of genes and telomeres. Here, the G4 formation decreases the replicative DNA at each cell cycle, finally leading to apoptosis. The ability to control this mitotic clock, particularly in cancer cells, is fascinating and passes through a rational understanding of the ligand/G4 interaction. We demonstrate that an accurate description of the ligand/G4 binding mechanism is possible using an innovative free-energy method called funnel-metadynamics (FM), which we have recently developed to investigate ligand/protein interaction. Using FM simulations, we have elucidated the binding mechanism of the anticancer alkaloid berberine to the human telomeric G4 (d[AG3(T2AG3)3]), computing also the binding free-energy landscape. Two ligand binding modes have been identified as the lowest energy states. Furthermore, we have found prebinding sites, which are preparatory to reach the final binding mode. In our simulations, the ions and the water molecules have been explicitly represented and the energetic contribution of the solvent during ligand binding evaluated. Our theoretical results provide an accurate estimate of the absolute ligand/DNA binding free energy (ΔGb0 = −10.3 ± 0.5 kcal/mol) that we validated through steady-state fluorescence binding assays. The good agreement between the theoretical and experimental value demonstrates that FM is a most powerful method to investigate ligand/DNA interaction and can be a useful tool for the rational design also of G4 ligands.

scholarly journals Influence of Mg2+ ions on the interaction between 3,5-dicaffeoylquinic acid and HTLV-I integrase

2012 ◽  
Vol 17 (1) ◽  
pp. 5 ◽  
Author(s):  
Ángela Peña ◽  
Juvenal Yosa ◽  
Yesid Cuesta-Astroz ◽  
Orlando Acevedo ◽  
Leonardo Lareo ◽  
...  
Keyword(s):  
Free Energy ◽  
Rational Design ◽  
Catalytic Domain ◽  
Binding Free Energy ◽  
Homology Model ◽  
Binding Mode ◽  
Antiretroviral Drugs ◽  
Type I ◽  
Interaction Sites ◽  
Dicaffeoylquinic Acid

<strong>Objective</strong>. Using molecular simulation, we studied the influence of Mg2+ ions on the binding mode of HTLV-I Integrase (IN) catalytic domain (modeled by homology) with the 3,5- Dicaffeoylquinic Acid (DCQA). HTLV-I Integrase homology model was built using template-like crystallographic data of the IN catalytic domain solved for Avian Sarcoma Virus (VSA, pdb: 1VSD). <strong>Materials and</strong> <strong>methods</strong>. In order to analyze the role of Mg2+ in the interaction or coupling between 3,5-DCQA and Integrase, three models were created: i) in the absence of Mg2+ ions, ii) with a Mg2+ ion coordinated at Asp15 and Asp72 and iii) model with two Mg2+ ions coordinated at Asp15-Asp72 and Asp72-Glu108. Coupling force and binding free energy between 3,5-DCQA and HTLV-I IN were assessed in the three models. <strong>Results</strong>. The lowest docking score and free energy binding were obtained for the second model. Mg2+ ion strongly affected the coupling of the inhibitor 3,5-DCQA with HTLV-I catalytic domain of Integrase, thus revealing a strong interaction in the ligand-protein complex regardless of the ligand-catalytic interaction sites for all three models. <strong>Conclusion</strong>. Altogether, these results strengthen the hypothesis that the presence of one Mg2+ ion could enhance the interaction in the complex by decreasing free energy, therefore increasing the affinity. Moreover, we propose 3, 5-DCQA as an important pharmacophore in the rational design of new antiretroviral drugs.<br /><br /><strong>Key words</strong>: 3,5 -Dicaffeoylquinic Acid, Human T-Lymphotropic Type I (HTLV-1), Integrase (IN), Homology Model, Molecular Docking, Binding Free Energy, Mg2+ Ions.

scholarly journals Virtual Screening and Free Energy Estimation for Identifying Mycobacterium Tuberculosis Flavoenzyme DprE1 Inhibitors

2020 ◽  
Author(s):  
Niranjan Kumar ◽  
Rakesh Srivastava ◽  
Amresh Prakash ◽  
Andrew M Lynn
Keyword(s):  
Free Energy ◽  
Mycobacterium Tuberculosis ◽  
Virtual Screening ◽  
Binding Free Energy ◽  
Md Simulations ◽  
Energy Estimation ◽  
Chemical Libraries ◽  
Drug Molecules ◽  
Rational Drug ◽  
Drug Designing

<p>we investigated the promising MTB drug target protein, DprE1 (decaprenylphosphoryl-β-d-ribose 2’-epimerase), involve in cell was synthesis of Mycobacterium tuberculosis and plays a crucial role<b> </b>in host pathogenesis, virulence, lethality and survival under stress. Considering the emergence of different variants of drug resistant MTB are one of the major threats worldwide which essentially requires more effective new drug molecules with no major side effects. Here, we employed comprehensive computational methods for the structure based virtual screening of bioactive anti-tuberculosis compounds from chemical libraries ChEMBL, characterized the physicochemical properties analyses and the trajectories obtained from MD simulations were used for estimation of binding free energy, applying molecular theory of solvation (MM/PBSA, MM/GBSA AND MM/3DRISM-KH). All results were compared with known DprE1 inhibitors. Our studies suggest that four compounds (ChEMBL2441313, ChEMBL2338605, ChEMBL441373 and ChEMBL1607606) compounds may be explored as lead molecules for the rational drug designing of DprE1-inhibitors in MTB therapy.</p><br>

scholarly journals Molecular Basis of Artemisinin Derivatives Inhibition of Myeloid Differentiation Protein 2 by Combined in Silico and Experimental Study

Molecules ◽  
2021 ◽  
Vol 26 (18) ◽  
pp. 5698
Author(s):  
Sennan Qiao ◽  
Hansi Zhang ◽  
Fei Sun ◽  
Zhenyan Jiang
Keyword(s):  
Free Energy ◽  
Hydrophobic Interactions ◽  
Binding Free Energy ◽  
Binding Mode ◽  
Experimental Results ◽  
Myeloid Differentiation ◽  
Inhibition Mechanism ◽  
Artemisinin Derivatives ◽  
Anti Inflammatory ◽  
Dynamics Simulations

Artemisinin (also known as Qinghaosu) , an active component of the Qinghao extract, is widely used as antimalarial drug. Previous studies reveal that artemisinin and its derivatives also have effective anti-inflammatory and immunomodulatory properties, but the direct molecular target remains unknown. Recently, several reports mentioned that myeloid differentiation factor 2 (MD-2, also known as lymphocyte antigen 96) may be the endogenous target of artemisinin in the inhibition of lipopolysaccharide signaling. However, the exact interaction between artemisinin and MD-2 is still not fully understood. Here, experimental and computational methods were employed to elucidate the relationship between the artemisinin and its inhibition mechanism. Experimental results showed that artemether exhibit higher anti-inflammatory activity performance than artemisinin and artesunate. Molecular docking results showed that artemisinin, artesunate, and artemether had similar binding poses, and all complexes remained stable throughout the whole molecular dynamics simulations, whereas the binding of artemisinin and its derivatives to MD-2 decreased the TLR4(Toll-Like Receptor 4)/MD-2 stability. Moreover, artemether exhibited lower binding energy as compared to artemisinin and artesunate, which is in good agreement with the experimental results. Leu61, Leu78, and Ile117 are indeed key residues that contribute to the binding free energy. Binding free energy analysis further confirmed that hydrophobic interactions were critical to maintain the binding mode of artemisinin and its derivatives with MD-2.

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