scholarly journals Ligand-Based Virtual Screening, Molecular Docking, Molecular Dynamics, and MM-PBSA Calculations towards the Identification of Potential Novel Ricin Inhibitors

Toxins ◽  
2020 ◽  
Vol 12 (12) ◽  
pp. 746 ◽  
Author(s):  
Fernanda D. Botelho ◽  
Marcelo C. dos Santos ◽  
Arlan da S. Gonçalves ◽  
Kamil Kuca ◽  
Martin Valis ◽  
...  
Keyword(s):  
Molecular Dynamics ◽  
Virtual Screening ◽  
Docking Studies ◽  
Chemical Weapon ◽  
Reference Molecule ◽  
Chemical Weapons Convention ◽  
Pubchem Database ◽  
Poisson Boltzmann ◽  
Castor Seeds ◽  
Dynamics Simulations

Ricin is a toxin found in the castor seeds and listed as a chemical weapon by the Chemical Weapons Convention (CWC) due to its high toxicity combined with the easiness of obtention and lack of available antidotes. The relatively frequent episodes of usage or attempting to use ricin in terrorist attacks reinforce the urge to develop an antidote for this toxin. In this sense, we selected in this work the current RTA (ricin catalytic subunit) inhibitor with the best experimental performance, as a reference molecule for virtual screening in the PubChem database. The selected molecules were then evaluated through docking studies, followed by drug-likeness investigation, molecular dynamics simulations and Molecular Mechanics Poisson–Boltzmann Surface Area (MM-PBSA) calculations. In every step, the selection of molecules was mainly based on their ability to occupy both the active and secondary sites of RTA, which are located right next to each other, but are not simultaneously occupied by the current RTA inhibitors. Results show that the three PubChem compounds 18309602, 18498053, and 136023163 presented better overall results than the reference molecule itself, showing up as new hits for the RTA inhibition, and encouraging further experimental evaluation.

Combined Virtual Screening, DFT Calculations and Molecular Dynamics Simulations to Discovery of Potent MMP-9 Inhibitors

2019 ◽  
Vol 16 (8) ◽  
pp. 892-903
Author(s):  
Hamed Bahrami ◽  
Hafezeh Salehabadi ◽  
Zahra Nazari ◽  
Massoud Amanlou
Keyword(s):  
Molecular Dynamics ◽  
Binding Energy ◽  
Virtual Screening ◽  
Dft Calculations ◽  
Molecular Dynamics Simulations ◽  
Density Functional ◽  
Docking Studies ◽  
Binding Energies ◽  
Energy Calculations ◽  
Dynamics Simulations

Background: Matrix metalloproteinase-9 (MMP-9) plays a crucial role in the development and progression of cancer. Therefore, identifying its inhibitors has enjoyed numerous attentions. In this report, a hybrid approach, including pharmacophore-based virtual screening, docking studies, and density functional theory (DFT) binding energy calculations followed by molecular dynamics simulations, was used to identify potential MMP-9 inhibitors. Methods: Pharmacophore modeling based on ARP101, as a known MMP-9 inhibitor, was performed and followed by virtual screening of ZINC database and docking studies to introduce a set of new ligands as candidates for potent inhibitors of MMP-9. The binding energies of MMP-9 and the selected ligands as well as ARP101, were estimated via the DFT energy calculations. Subsequently, molecular dynamics simulations were applied to evaluate and compare the behavior of ARP101 and the selected ligand in a dynamic environment. Results: (S,Z)-6-(((2,3-dihydro-1H-benzo[d]imidazol-2-yl)thio)methylene)-2-((4,6,7- trimethylquinazolin- 2-yl)amino)-1,4,5,6-tetrahydropyrimidin-4-ol, ZINC63611396, with the largest DFT binding energy, was selected as a proper potent MMP-9 inhibitor. Molecular dynamics simulations indicated that the new ligand was stable in the active site. Conclusion: The results of this study revealed that compared to the binding energies achieved from the docking studies, the binding energies obtained from the DFT calculations were more consistent with the intermolecular interactions. Also, the interaction between the Zinc ion and ligand, in particular the Zn2+-ligand distance, played a profound role in the quantity of DFT binding energies.

scholarly journals Sampling of conformational ensemble for virtual screening using molecular dynamics simulations and normal mode analysis

2015 ◽  
Vol 7 (17) ◽  
pp. 2317-2331 ◽  
Author(s):  
Gautier Moroy ◽  
Olivier Sperandio ◽  
Shakti Rielland ◽  
Saurabh Khemka ◽  
Karen Druart ◽  
...  
Keyword(s):  
Molecular Dynamics ◽  
Virtual Screening ◽  
Molecular Dynamics Simulations ◽  
Normal Mode ◽  
Normal Mode Analysis ◽  
Mode Analysis ◽  
Conformational Ensemble ◽  
Dynamics Simulations

scholarly journals Amino Alcohols from Eugenol as Potential Semisynthetic Insecticides: Chemical, Biological, and Computational Insights

Molecules ◽  
2021 ◽  
Vol 26 (21) ◽  
pp. 6616
Author(s):  
Renato B. Pereira ◽  
Nuno F. S. Pinto ◽  
Maria José G. Fernandes ◽  
Tatiana F. Vieira ◽  
Ana Rita O. Rodrigues ◽  
...  
Keyword(s):  
Molecular Dynamics ◽  
Biological Activity ◽  
Virtual Screening ◽  
Serine Proteases ◽  
Insect Cells ◽  
Amino Alcohols ◽  
Odorant Binding Proteins ◽  
Synthetic Pesticide ◽  
Dynamics Simulations ◽  
Odorant Binding

A series of β-amino alcohols were prepared by the reaction of eugenol epoxide with aliphatic and aromatic amine nucleophiles. The synthesized compounds were fully characterized and evaluated as potential insecticides through the assessment of their biological activity against Sf9 insect cells, compared with a commercial synthetic pesticide (chlorpyrifos, CHPY). Three derivatives bearing a terminal benzene ring, either substituted or unsubstituted, were identified as the most potent molecules, two of them displaying higher toxicity to insect cells than CHPY. In addition, the most promising molecules were able to increase the activity of serine proteases (caspases) pivotal to apoptosis and were more toxic to insect cells than human cells. Structure-based inverted virtual screening and molecular dynamics simulations demonstrate that these molecules likely target acetylcholinesterase and/or the insect odorant-binding proteins and are able to form stable complexes with these proteins. Encapsulation assays in liposomes of DMPG and DPPC/DMPG (1:1) were performed for the most active compound, and high encapsulation efficiencies were obtained. A thermosensitive formulation was achieved with the compound release being more efficient at higher temperatures.

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