scholarly journals Doxorubicin Encapsulation in Carbon Nanotubes Having Haeckelite or Stone–Wales Defects as Drug Carriers: A Molecular Dynamics Approach

Molecules ◽  
2021 ◽  
Vol 26 (6) ◽  
pp. 1586
Author(s):  
Leonor Contreras ◽  
Ignacio Villarroel ◽  
Camila Torres ◽  
Roberto Rozas
Keyword(s):  
Carbon Nanotubes ◽  
Molecular Dynamics ◽  
Drug Delivery Systems ◽  
Nitrogen Doping ◽  
Drug Carriers ◽  
Acidic Ph ◽  
Free Energies ◽  
Interaction Forces ◽  
Chiral Nanotubes ◽  
Binding Free Energies

Doxorubicin (DOX), a recognized anticancer drug, forms stable associations with carbon nanotubes (CNTs). CNTs when properly functionalized have the ability to anchor directly in cancerous tumors where the release of the drug occurs thanks to the tumor slightly acidic pH. Herein, we study the armchair and zigzag CNTs with Stone–Wales (SW) defects to rank their ability to encapsulate DOX by determining the DOX-CNT binding free energies using the MM/PBSA and MM/GBSA methods implemented in AMBER16. We investigate also the chiral CNTs with haeckelite defects. Each haeckelite defect consists of a pair of square and octagonal rings. The armchair and zigzag CNT with SW defects and chiral nanotubes with haeckelite defects predict DOX-CNT interactions that depend on the length of the nanotube, the number of present defects and nitrogen doping. Chiral nanotubes having two haeckelite defects reveal a clear dependence on the nitrogen content with DOX-CNT interaction forces decreasing in the order 0N > 4N > 8N. These results contribute to a further understanding of drug-nanotube interactions and to the design of new drug delivery systems based on CNTs.

scholarly journals Carbon Nanotubes Having Haeckelite Defects as Potential Drug Carriers. Molecular Dynamics Simulation

Molecules ◽  
2019 ◽  
Vol 24 (23) ◽  
pp. 4281
Author(s):  
Camila Torres ◽  
Ignacio Villarroel ◽  
Roberto Rozas ◽  
Leonor Contreras
Keyword(s):  
Carbon Nanotubes ◽  
Drug Delivery Systems ◽  
Nitrogen Doping ◽  
External Surface ◽  
Drug Carriers ◽  
Dynamics Simulation ◽  
Acidic Ph ◽  
Free Energies ◽  
Nanotube Chirality ◽  
Binding Free Energies

Carbon nanotubes (CNTs) are valuable drug carriers since when properly functionalized they transport drugs and anchor directly to cancerous tumors whose more acidic pH causes the drug release. Herein, we study the so-called zigzag and armchair CNTs with haeckelite defects to rank their ability to adsorb doxorubicin (DOX) by determining the DOX-CNT binding free energies using the MM/PBSA and MM/GBSA methods implemented in AMBER. Our results reveal stronger DOX-CNT interactions for encapsulation of the drug inside the nanotube compared to its adsorption onto the defective nanotube external surface. Armchair CNTs with one and two defects exhibit better results compared with those with four and fifteen defects. Each haeckelite defect consists of a pair of square and octagonal rings. DOX-CNT binding free energies are predicted to be dependent on: (i) nanotube chirality and diameter, (ii) the number of defects, (iii) nitrogen doping and (iv) the position of the encapsulated DOX inside the nanotube. Armchair (10,10) nanotubes with two haeckelite defects, doped with nitrogen, exhibit the best drug-nanotube binding free energies compared with zigzag and fully hydrogenated nanotubes and, also previously reported ones with bumpy defects. These results contribute to further understanding drug-nanotube interactions and their potential application to the design of new drug delivery systems.

scholarly journals Protocols Utilizing Constant pH Molecular Dynamics to Compute pH-Dependent Binding Free Energies

2014 ◽  
Vol 119 (3) ◽  
pp. 861-872 ◽  
Author(s):  
M. Olivia Kim ◽  
Patrick G. Blachly ◽  
Joseph W. Kaus ◽  
J. Andrew McCammon
Keyword(s):  
Molecular Dynamics ◽  
Free Energies ◽  
Constant Ph ◽  
Ph Dependent ◽  
Constant Ph Molecular Dynamics ◽  
Binding Free Energies

Investigations on the mechanisms of interactions between matrix metalloproteinase 9 and its flavonoid inhibitors using a combination of molecular docking, hybrid quantum mechanical/molecular mechanical calculations, and molecular dynamics simulations

2014 ◽  
Vol 92 (9) ◽  
pp. 821-830 ◽  
Author(s):  
Zhi-Guang Zhou ◽  
Qi-Zheng Yao ◽  
Dong Lei ◽  
Qing-Qing Zhang ◽  
Ji Zhang
Keyword(s):  
Molecular Dynamics ◽  
Molecular Docking ◽  
Molecular Dynamics Simulations ◽  
Biological Activities ◽  
Dynamics Simulation ◽  
Quantum Mechanical ◽  
Free Energies ◽  
Hydrogen Bond Networks ◽  
Dynamics Simulations ◽  
Binding Free Energies

Many experimental studies have found that flavonoids can inhibit the activities of matrix metalloproteinases (MMPs), but the relevant mechanisms are still unclear. In this paper, the interaction mechanisms of MMP-9 with its five flavonoid inhibitors are investigated using a combination of molecular docking, hybrid quantum mechanical and molecular mechanical (QM/MM) calculations, and molecular dynamics simulations. The molecular dynamics simulation results show a good linear correlation between the calculated binding free energies of QM/MM−Poisson–Boltzmann surface area (PBSA) and the experimental −log(EC50) regarding the studied five flavonoids on MMP-9 inhibition in explicit solvent. It is found that compared with the MM−PBSA method, the QM/MM−PBSA method can obviously improve the accuracy for the calculated binding free energies. The predicted binding modes of the five flavonoid−MMP-9 complexes reveal that the different hydrogen bond networks can form besides producing the Zn−O coordination bonds, which can reasonably explain previous experimental results. The agreement between our calculated results and the previous experimental facts indicates that the force field parameters used here are effective and reliable for investigating the systems of flavonoid−MMP-9 interactions, and thus, these simulations and analyses could be reproduced for the other related systems involving protein−ligand interactions. This paper may be helpful for designing the new MMP-9 inhibitors having higher biological activities by carrying out the structural modifications of flavonoid molecules.

scholarly journals Alchemical Free Energy Estimators and Molecular Dynamics Engines: Accuracy, Precision and Reproducibility

2021 ◽  
Author(s):  
Alexander Wade ◽  
Agastya Bhati ◽  
Shunzhou Wan ◽  
Peter Coveney
Keyword(s):  
Molecular Dynamics ◽  
Free Energy ◽  
Binding Free Energy ◽  
Thermodynamic Integration ◽  
Free Energy Perturbation ◽  
Free Energies ◽  
Ensemble Averaging ◽  
Relative Binding ◽  
Energy Perturbation ◽  
Binding Free Energies

The binding free energy between a ligand and its target protein is an essential quantity to know at all stages of the drug discovery pipeline. Assessing this value computationally can offer insight into where efforts should be focused in the pursuit of effective therapeutics to treat myriad diseases. In this work we examine the computation of alchemical relative binding free energies with an eye to assessing reproducibility across popular molecular dynamics packages and free energy estimators. The focus of this work is on 54 ligand transformations from a diverse set of protein targets: MCL1, PTP1B, TYK2, CDK2 and thrombin. These targets are studied with three popular molecular dynamics packages: OpenMM, NAMD2 and NAMD3. Trajectories collected with these packages are used to compare relative binding free energies calculated with thermodynamic integration and free energy perturbation methods. The resulting binding free energies show good agreement between molecular dynamics packages with an average mean unsigned error between packages of 0.5 $kcal/mol$ The correlation between packages is very good with the lowest Spearman's, Pearson's and Kendall's tau correlation coefficient between two packages being 0.91, 0.89 and 0.74 respectively. Agreement between thermodynamic integration and free energy perturbation is shown to be very good when using ensemble averaging.

Virtual Screening-Based Discovery of Potent Hypoglycemic Agents: In Silico, Chemical Synthesis and Biological Study

2019 ◽  
Vol 15 ◽  
Author(s):  
Mohammed A. Khedr ◽  
Omar M. M. Mohafez ◽  
Ibrahim A. Al-Haider
Keyword(s):  
Diabetes Mellitus ◽  
Molecular Dynamics ◽  
Virtual Screening ◽  
Molecular Dynamics Simulations ◽  
Hypoglycemic Agents ◽  
Type Ii ◽  
Free Energies ◽  
Diabetes Mellitus Type Ii ◽  
Dynamics Simulations ◽  
Binding Free Energies

Background: Dipeptidyl peptidase IV has been reported to be an important target for the development and discovery of new therapies for diabetes mellitus type II. Objective: The main aim of this study is to discover chemical entities that target the inhibition of DPP IV and feature potent hypoglycemic action. Methods: A structure-based virtual screening was applied to discover new hypoglycemic agents. Molecular docking was performed to compute the binding free energies. Molecular dynamics simulations was done to evaluate the binding stability of resulted hits. Results: Seven small non-peptide potential inhibitors of Dipeptidyl peptidase IV with 3-imino-4-(4-substituted phenyl)-1, 2, 5-thiadiazolidine-1,1-dioxide scaffold that were discovered. The binding free energies ranged from -24.50 to -36.06 kJ/mol. Molecular dynamics simulations revealed high stability of all protein-ligand complexes with low root mean square deviation over 10 ns simulation time. The tested compounds expressed a significant reduction in blood glucose level up to 90% with excellent oral glucose tolerance test after 120 minutes of injection in a diabetes mellitus type II animal model. A promising release of insulin was observed with a potential hypoglycemic activity for all compounds. Conclusion: The virtual screening was successful to discover potent hypoglycemic agents with drug-like properties that may need more consideration for future studies and development.

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