scholarly journals Proposition of a new allosteric binding site for potential SARS-CoV-2 3CL protease inhibitors by utilizing molecular dynamics simulations and ensemble docking

2020 ◽  
Author(s):  
Jurica Novak ◽  
Hrvoje Rimac ◽  
Shivananda Kandagalla ◽  
Prateek Pathak ◽  
Maria Grishina ◽  
...  
Keyword(s):  
Molecular Dynamics ◽  
Binding Site ◽  
Dynamics Simulation ◽  
Structural Proteins ◽  
Crystallographic Structure ◽  
Ensemble Docking ◽  
Covalent Inhibitors ◽  
Dynamics Simulations ◽  
3Cl Protease ◽  
Drugbank Database

Abstract The SARS-CoV-2 3CL protease shows a high similarity with 3CL proteases of other beta-coronaviruses, such as SARS and MERS. It is the main enzyme involved in generating various non-structural proteins that are important for viral replication and is one of the most important proteins responsible for SARS-CoV-2 virulence. In this study, we have conducted ensemble docking of molecules from the DrugBank database using both crystallographic structure of the SARS-CoV-2 3CLpro, as well as five conformations obtained after performing a cluster analysis of a 300 ns molecular dynamics simulation. This procedure elucidated the inappropriateness of the active site for non-covalent inhibitors, but it has also shown that there exists an additional, more favorable, allosteric binding site, which could be a better target for non-covalent inhibitors, as it could prevent dimerization and activation of SARS-CoV-2 3CLpro.

scholarly journals Design of a New α-1-C-Alkyl-DAB Derivative Acting as a Pharmacological Chaperone for β-Glucocerebrosidase Using Ligand Docking and Molecular Dynamics Simulation

Molecules ◽  
2018 ◽  
Vol 23 (10) ◽  
pp. 2683 ◽  
Author(s):  
Izumi Nakagome ◽  
Atsushi Kato ◽  
Noriyuki Yamaotsu ◽  
Tomoki Yoshida ◽  
Shin-ichiro Ozawa ◽  
...  
Keyword(s):  
Molecular Dynamics ◽  
Binding Site ◽  
Binding Affinity ◽  
Gaucher Disease ◽  
Point Mutations ◽  
Dynamics Simulation ◽  
Ligand Docking ◽  
Pharmacological Chaperone ◽  
Pharmacological Chaperones ◽  
Dynamics Simulations

Some point mutations in β-glucocerebrosidase cause either improper folding or instability of this protein, resulting in Gaucher disease. Pharmacological chaperones bind to the mutant enzyme and stabilize this enzyme; thus, pharmacological chaperone therapy was proposed as a potential treatment for Gaucher disease. The binding affinities of α-1-C-alkyl 1,4-dideoxy-1,4-imino-d-arabinitol (DAB) derivatives, which act as pharmacological chaperones for β-glucocerebrosidase, abruptly increased upon elongation of their alkyl chain. In this study, the primary causes of such an increase in binding affinity were analyzed using protein–ligand docking and molecular dynamics simulations. We found that the activity cliff between α-1-C-heptyl-DAB and α-1-C-octyl-DAB was due to the shape and size of the hydrophobic binding site accommodating the alkyl chains, and that the interaction with this hydrophobic site controlled the binding affinity of the ligands well. Furthermore, based on the aromatic/hydrophobic properties of the binding site, a 7-(tetralin-2-yl)-heptyl-DAB compound was designed and synthesized. This compound had significantly enhanced activity. The design strategy in consideration of aromatic interactions in the hydrophobic pocket was useful for generating effective pharmacological chaperones for the treatment of Gaucher disease.

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 Prediction of Ciclesonide Binding Site on Middle-East Respiratory Syndrome Coronavirus Nsp15 Multimer by Molecular Dynamics Simulations

2021 ◽  
Author(s):  
Shun Sakuraba ◽  
Hidetoshi Kono
Keyword(s):  
Molecular Dynamics ◽  
Molecular Dynamics Simulation ◽  
Middle East ◽  
Molecular Dynamics Simulations ◽  
Binding Site ◽  
Molecular Mechanism ◽  
Middle East Respiratory Syndrome ◽  
Dynamics Simulation ◽  
Dynamics Simulations

Ciclesonide, a corticosteroid, was known to inhibit the growth of Middle-east respiratory syndrome (MERS) coronavirus. However, its molecular mechanism was unknown. We tried to uncover the molecular mechanism from the molecular dynamics simulation.<div>SARS_CoV_2_nsp15.pdf: The preprint document.</div><div>nsp15-mers-supp.zip: Supplemental data including binding poses and parameter files for the simulation.</div>

scholarly journals Prediction of Ciclesonide Binding Site on Middle-East Respiratory Syndrome Coronavirus Nsp15 Multimer by Molecular Dynamics Simulations

2021 ◽  
Author(s):  
Shun Sakuraba ◽  
Hidetoshi Kono
Keyword(s):  
Molecular Dynamics ◽  
Molecular Dynamics Simulation ◽  
Middle East ◽  
Molecular Dynamics Simulations ◽  
Binding Site ◽  
Molecular Mechanism ◽  
Middle East Respiratory Syndrome ◽  
Dynamics Simulation ◽  
Dynamics Simulations

Ciclesonide, a corticosteroid, was known to inhibit the growth of Middle-east respiratory syndrome (MERS) coronavirus. However, its molecular mechanism was unknown. We tried to uncover the molecular mechanism from the molecular dynamics simulation.<div>SARS_CoV_2_nsp15.pdf: The preprint document.</div><div>nsp15-mers-supp.zip: Supplemental data including binding poses and parameter files for the simulation.</div>

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>

EFFECT OF pH ON STRUCTURE AND STABILITY OF COLLAGEN-LIKE PEPTIDE: INSIGHT FROM MOLECULAR DYNAMICS SIMULATION

2011 ◽  
Vol 10 (02) ◽  
pp. 245-259 ◽  
Author(s):  
SHANG-ZHI PU ◽  
WEN-HUA ZHANG ◽  
BI SHI
Keyword(s):  
Molecular Dynamics ◽  
Amino Acid ◽  
Force Field ◽  
Dynamics Simulation ◽  
Side Chain ◽  
Crystallographic Structure ◽  
Amino Acid Residues ◽  
Effect Of Ph ◽  
Structure And Stability ◽  
Dynamics Simulations

Molecular dynamics simulations were carried out to investigate the effect of pH on structure and stability of collagen-like peptide. All simulations were performed using the consistent valence force field (CVFF) molecular mechanical force field and isothermal-isobaric ensemble (NPT). The initial geometries of the collagen-like peptide were from an X-ray crystallographic structure. Some analyses from the molecular dynamics trajectories have been completed. The results show that the diameter of collagen-like peptide increases and the volume swells obviously in basic environment; however, the size of peptide changes slightly in acidic environment. The stability of collagen-like peptide decreases in acid and basic environment comparing to neutral environment based on root mean square deviation (RMSD). The number of hydrogen bond formed by peptide has a tendency to decrease in both acidic and basic environment. The average of intra-molecular H-bond is minimal under basic condition, and the average of inter-molecular H-bond between amino acid residues and water molecules is minimal under acid condition. The radial distribution function (RDF) shows that side-chain oxygen atoms are easier to form hydrogen bonds with water than side-chain nitrogen atoms. The interaction of various amino acid residues with water is position dependent. Distance between two triple helices increases markedly under highly basic condition, but changes slightly under highly acidic condition.

Unveiling the Structural Insights into the Selective Inhibition of Protein Kinase D1

2019 ◽  
Vol 25 (10) ◽  
pp. 1059-1074 ◽  
Author(s):  
Raju Dash ◽  
Md. Arifuzzaman ◽  
Sarmistha Mitra ◽  
Md. Abdul Hannan ◽  
Nurul Absar ◽  
...  
Keyword(s):  
Molecular Dynamics ◽  
Molecular Dynamics Simulation ◽  
Protein Kinase ◽  
Binding Site ◽  
Free Energy Calculations ◽  
Dynamics Simulation ◽  
Selective Inhibitors ◽  
Conserved Residues ◽  
Protein Kinase D1 ◽  
Binding Mechanisms

Background: Although protein kinase D1 (PKD1) has been proved to be an efficient target for anticancer drug development, lack of structural details and substrate binding mechanisms are the main obstacles for the development of selective inhibitors with therapeutic benefits. Objective: The present study described the in silico dynamics behaviors of PKD1 in binding with selective and non-selective inhibitors and revealed the critical binding site residues for the selective kinase inhibition. Methods: Here, the three dimensional model of PKD1 was initially constructed by homology modeling along with binding site characterization to explore the non-conserved residues. Subsequently, two known inhibitors were docked to the catalytic site and the detailed ligand binding mechanisms and post binding dyanmics were investigated by molecular dynamics simulation and binding free energy calculations. Results: According to the binding site analysis, PKD1 serves several non-conserved residues in the G-loop, hinge and catalytic subunits. Among them, the residues including Leu662, His663, and Asp665 from hinge region made polar interactions with selective PKD1 inhibitor in docking simulation, which were further validated by the molecular dynamics simulation. Both inhibitors strongly influenced the structural dynamics of PKD1 and their computed binding free energies were in accordance with experimental bioactivity data. Conclusion: The identified non-conserved residues likely to play critical role on molecular reorganization and inhibitor selectivity. Taken together, this study explained the molecular basis of PKD1 specific inhibition, which may help to design new selective inhibitors for better therapies to overcome cancer and PKD1 dysregulated disorders.

Design of Inhibitors for Glyceraldehyde-3-phosphate Dehydrogenase (GAPDH) Enzyme of Leishmania mexicana

2020 ◽  
Vol 16 (6) ◽  
pp. 784-795
Author(s):  
Krisnna M.A. Alves ◽  
Fábio José Bonfim Cardoso ◽  
Kathia M. Honorio ◽  
Fábio A. de Molfetta
Keyword(s):  
Molecular Dynamics ◽  
Molecular Dynamics Simulations ◽  
Binding Site ◽  
Point Of View ◽  
New Drugs ◽  
Leishmania Mexicana ◽  
Receptor Complexes ◽  
Starting Point ◽  
Dynamics Simulations ◽  
Selection Of

Background:: Leishmaniosis is a neglected tropical disease and glyceraldehyde 3- phosphate dehydrogenase (GAPDH) is a key enzyme in the design of new drugs to fight this disease. Objective:: The present study aimed to evaluate potential inhibitors of GAPDH enzyme found in Leishmania mexicana (L. mexicana). Methods: A search for novel antileishmanial molecules was carried out based on similarities from the pharmacophoric point of view related to the binding site of the crystallographic enzyme using the ZINCPharmer server. The molecules selected in this screening were subjected to molecular docking and molecular dynamics simulations. Results:: Consensual analysis of the docking energy values was performed, resulting in the selection of ten compounds. These ligand-receptor complexes were visually inspected in order to analyze the main interactions and subjected to toxicophoric evaluation, culminating in the selection of three compounds, which were subsequently submitted to molecular dynamics simulations. The docking results showed that the selected compounds interacted with GAPDH from L. mexicana, especially by hydrogen bonds with Cys166, Arg249, His194, Thr167, and Thr226. From the results obtained from molecular dynamics, it was observed that one of the loop regions, corresponding to the residues 195-222, can be related to the fitting of the substrate at the binding site, assisting in the positioning and the molecular recognition via residues responsible for the catalytic activity. Conclusion:: he use of molecular modeling techniques enabled the identification of promising compounds as inhibitors of the GAPDH enzyme from L. mexicana, and the results obtained here can serve as a starting point to design new and more effective compounds than those currently available.

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