Engineered nanoparticles as Selinexor drug delivery systems across the cell membrane and related signaling pathways in cancer cells.

In the present work, molecular dynamics simulation is applied to evaluate the drug carrier efficiency of graphene oxide nanoflake (GONF) for loading of Selinexor (SXR) drug as well as the drug delivery by 2D material through the membrane in aqueous solution. In addition, to investigate the adsorption and penetration of drug-nanocarrier complex into the cell membrane, well-tempered metadynamics simulations and steered molecular dynamics (SMD) simulations were performed. Based on the obtained results, it is evident that intermolecular hydrogen bonds (HBs) and π-π interactions play a significant role in expediting the interaction between drug molecules and the graphene oxide (GO) nanosheet, ultimately resulting in the formation of a stable SXR-GO complex. The Lennard-Jones (L-J) energy value for the interaction of SXR with GONF is calculated to be approximately -98.85 kJ/mol. In the SXR-GONF complex system, the dominant interaction between SXR and GONF is attributed to the L-J term, resulting from the formation of a strong π-π interaction between the drug molecules and the substrate surface. Moreover, our simulations show by decreasing the distance of GONF with respect to cell membrane, the interaction energy of GONF-membrane significantly decrease to -1500 kJ/mol resulting in fast diffusion of SXR-GONF complex toward the bilayer surface that is favored opening the way to natural drug nanocapsule.

Engineering of surface-modified CuBTC-MXene nanocarrier for adsorption and co-loading of curcumin/paclitaxel from aqueous solutions for synergistic multi-therapy of cancer.

Two-dimensional (2D) nanomaterials can improve drug delivery by reducing toxicity, increasing bioavailability and boosting efficacy. In this study, the simultaneous use of transition metal carbides and nitrides (MXenes) along with copper (II) benzene-1, 3, 5-tricarboxylate metal-organic framework (Cu - BTC/MOF) as attractive nanocarriers are investigated for loading and delivering curcumin (CUR) and paclitaxel (PTX) drugs to cancer cells. The efficiency of surface termination (bare and oxygen) in the adsorption of PTX and CUR drugs and the co-loading of these two drugs are evaluated. Our results show that the strongest interaction energy belongs to the adsorption of drug CUR on the MXNNO-Cu-BTC adsorbent, while the interaction of PTX drug with the MXNO- Cu-BTC in the MXNO-Cu-BTC/PTX&CUR system is the lowest due to the particular structure of the drug and the adsorbent. Our results show that at the beginning simulation, the interaction energy between the PTX drug and water in PTX/MXN system is -4645.48 kJ/mol, which reduces to -3848.71 kJ/mol after the system reaches equilibrium. Therefore, the inspected adsorbents have a good performance in adsorbing CUR and PTX drugs. The obtained results from this investigation provide valuable information about experimental studies by medical scientists in the future.Communicated by Ramaswamy H. Sarma.

Toward efficient electrodes for a high-performance fast-charge Li-ion battery: molecular dynamics simulation and DFT calculations.

Due to the increasing demand for electrochemical energy storage, rechargeable lithium-ion batteries (LIBs) are gaining more and more attention. However, much research still needs to be conducted to enhance their cycling and storage capacity. Recently, computational studies have provided valuable information for LIB development, which is very difficult and expensive to obtain experimentally. In this study, molecular dynamics (MD) simulation and first-principles calculations are performed to investigate the potential of a Cu-BHT MOF and phosphorene as the cathode and anode, respectively. An external electrical field is applied to simulate the charging process and study lithium-ion behavior during migration from the cathode to the anode in an electrolyte. Time and space-dependent variables such as energy, radial distribution function, mean square displacement (MSD), density, and so on have been used to evaluate the studied system. The MSD calculations showed that there are two different regimes in the MSD curves of Li-ions; diffusion and cage. In the designed LIB, the cathode has a better performance in the presence of a high electric field, whereas under an external electric field of 1.5 V Å-1, more lithium ions move from the cathode to the anode. By using first-principles calculations the lithium insertion in phosphorene and Cu-BHT is studied in various configurations and concentrations. The obtained results indicated that the adsorption energy of lithium on the cathode in the most stable configuration is -3.21 eV which is enough to prevent the clustering effect. Furthermore, the interaction of Li with phosphorene is strong enough and forms a stable complex. It is found that by insertion of Li into the anode the band gap is decreased which indicates the possibility of fast charging of LIBs. Investigation of different concentrations of ions reveals that the Li-Li repulsive interactions lead to a decrease in the adsorption energy of Li with the anode and cathode. The results of this study provide an in-depth insight into LIBs.

State-of-the-art predictive modeling of heavy metal ions removal from the water environment using nanotubes.

In this research, molecular dynamics (MD) simulation is used to investigate the efficiency of carbon nanotubes (CNT) and boron nitride nanotubes (BNNT) in removing lead ions from contaminated waters. Then the effect of functionalizing nanotubes with -COO- and COOH- functional groups and the nanotubes' absorption performance of two different concentrations of lead ions are studied. To better evaluate adsorption process, the set of descriptors, such as interaction energies, radial distribution function, etc., are calculated. The MD results show that the absorption performance is significantly improved by modifying the surface of CNT and BNNT with functional groups. In addition, the adsorption capacity increases in higher concentrations of Pb ions at BNNTCOO- and CNTCOOH systems. The interaction energy of BNNTCOO- with a concentration of 50 lead ions is - 2879.28 kJ/mol, which is about 106 kJ/mol more negative than BNNTCOO- at a concentration of 20 lead ions. Also, it is observed that the functionalization of both nanotubes with -COO- increases their absorption capacity. The obtained results from this study provide significant information about the mechanisms of lead adsorption on the surface of nanotubes.

Graphene Oxide Hosting a pH-Sensitive Prodrug: An In Silico Investigation of Graphene Oxide-Based Nanovehicle toward Cancer Therapy.

Prodrug and drug delivery systems are two effective strategies for improving the selectivity of chemotherapeutics. Herein, via molecular dynamics (MD) simulation and free energy calculation, the effectiveness of the graphene oxide (GO) decorated with the pH-sensitive prodrug (PD) molecules in cancer therapy is investigated. PEI-CA-DOX (prodrug) was loaded onto the GO surface, in which the hydrogen bonding and pi-pi stacking interactions play the main role in the stability of the GO-PD complex. Due to the strong interaction of GO and PD (about -800 kJ/mol), the GO-PD complex remains stable during the membrane penetration process. The obtained results confirm that GO is a suitable surface for hosting the prodrug and passing it through the membrane. Furthermore, the investigation of the release process shows that the PD can be released under acidic conditions. This phenomenon is due to the reduction of the contribution of electrostatic energy in the GO and PD interaction and the entry of water into the drug delivery system. Moreover, it is found that an external electrical field does not have much effect on drug release. Our results provide a deep understanding of the prodrug delivery systems, which helps the combination of nanocarriers and modified chemotherapy drugs in the future.

Validation of an MD simulation approach for electrical field responsive micelles and their application in drug delivery.

In the current work, a new type of micelle is designed that has active connectivity in respond to exterior stimulus and the desired water solubility. Two end-ornamented homopolymers, polystyrene-beta-cyclodextrin (PS-ß-CD) and polyethylene oxide-ferrocene (PE-FE), can aggregate as a supramolecular micelle (PS-ß-CD/PE-FE) by the guest-host interactions. Our results showed that the Lennard-Jones and hydrophobic interactions are the main powerful forces for the micelle formation process. It was found that the electrical field plays a role as a driving force in the reversible assembly-disassembly of the micellar system. Moreover, for the first time, we examined the PS-ß-CD/PE-FE micelle interaction as a drug delivery system with anastrozole (ANS) and mitomycin C (MIC) anti-cancer drugs. The investigation of the total energy between PS-ß-CD/PE-FE micelle and drugs predicts the drug adsorption process as favorable (Etotal = - 638.67 and - 259.80 kJ/mol for the Micelle@ANS and Micelle@MIC complexes, respectively). Our results offer a deep understanding of the micelle formation process, the electrical field-respond, and drug adsorption behaviors of the micelle. This simulation study has been accomplished by employing classical molecular dynamics calculation.

Surface functionalization of graphene nanosheet with poly (L-histidine) and its application in drug delivery: covalent vs non-covalent approaches.

Nowadays, nanomaterials are increasingly being used as drug carriers in the treatment of different types of cancers. As a result, these applications make them attractive to researchers dealing with diagnosis and biomarkers discovery of the disease. In this study, the adsorption behavior of gemcitabine (GMC) on graphene nanosheet (GNS), in the presence and absence of Poly (L-histidine) (PLH) polymer is discussed using molecular dynamics (MD) simulation. The MD results revealed an increase in the efficiency and targeting of the drug when the polymer is covalently attached to the graphene substrate. In addition, the metadynamics simulation to investigate the effects of PLH on the adsorption capacity of the GNS, and explore the adsorption/desorption process of GMC on pristine and PLH- grafted GNS is performed. The metadynamics calculations showed that the amount of free energy of the drug in acidic conditions is higher (- 281.26 kJ/mol) than the free energy in neutral conditions (- 346.24 kJ/mol). Consequently, the PLH polymer may not only help drug adsorption but can also help in drug desorption in lower pH environments. Based on these findings, it can be said that covalent polymer bonding not only can help in the formation of a targeted drug delivery system but also can increase the adsorption capacity of the substrate.

Interactions of boron nitride nanosheet with amino acids of differential polarity.

Free amino acids represent a category of different biomolecules in the blood plasma, which bond together to make up larger organic molecules such as peptides and proteins. Their interactions with biocompatible nanoparticles are especially important for plasma-related biomedical applications. Among the various nanomaterials, the applications of carbon and boron nitride-based nanotubes/nanosheets have shown a huge increase in recent years. The effect of molecular polarity on the interaction between a boron nitride nanosheet (BNNS) and amino acids is investigated with quantum mechanical calculations by density functional theory (DFT), classical MD simulations, and well-tempered metadynamics simulations. Four representative amino acids, namely, alanine (Ala), a nonpolar amino acid, and aspartic acid (Asp), lysine (Lys) and serine (Ser), three polar amino acids are considered for their interactions with BNNS. In DFT calculations, the values of the adsorption energies for Lys-BNNS and Ser-BNNS complexes are - 48.32 and - 32.89 kJ/mol, respectively, which are more stable than the other cases. Besides, the adsorption energy calculated confirms the exergonic reactions for all investigated systems; it implied that the interaction is favorable electronically. The MD results show that the LYS molecules have a higher attraction toward BNNS because of its alkane tail in its side chain, and the ASP revealed the repulsion force originating from its COO- group. All the results are confirmed by free energy analyzes in which the LYS showed the highest adsorption free energy at a relatively farther distance than other complexes. In fact, our results revealed the contribution of functional groups and backbone of the amino acids in the adsorption or repulsion features of the studied systems.

Insights into glyphosate removal efficiency using a new 2D nanomaterial.

Glyphosate (GLY) is a nonselective herbicide that has been widely used in agriculture for weed control. However, there are potential genetic, development and reproduction risks to humans and animals associated with exposure to GLY. Therefore, the removal of this type of environmental pollutants has become a significant challenge. Some of the two-dimensional nanomaterials, due to the characteristics of hydrophilic nature, abundant highly active surficial sites and, large specific surface area are showed high removal efficiency for a wide range of pollutants. The present study focused on the adsorption behavior of GLY on silicene nanosheets (SNS). In order to provide more detailed information about the adsorption mechanism of contaminants on the adsorbent's surface, molecular dynamics (MD) and well-tempered metadynamics simulations are performed. The MD results are demonstrated that the contribution of the L-J term in pollutant/adsorbent interactions is more than coulombic energy. Furthermore, the simulation results demonstrated the lowest total energy value for system-A (with the lowest pollutant concentration), while system-D (contains the highest concentration of GLY) had the most total energy (E tot: -78.96 vs. -448.51 kJ mol-1). The well-tempered metadynamics simulation is accomplished to find the free energy surface of the investigated systems. The free energy calculation for the SNS/GLY system indicates a stable point in which the distance of GLY from the SNS surface is 1.165 nm.

Development of the poly(l-histidine) grafted carbon nanotube as a possible smart drug delivery vehicle.

Polyhistidine is among the cell-penetrating peptides that in an acidic environment can facilitate membrane transition. Keeping in mind that the pH of the tumor intercellular medium is ∼5.5, in this paper, we examined the functionalization of a convenient drug delivery vehicle with cell-penetrating poly(l-histidine) to provide a smart drug delivery system. Classical molecular dynamics and metadynamics simulations are used to investigate the interactions between doxorubicin, carbon nanotube, poly(l-histidine), and the cell membrane. Metadynamics simulation revealed that not only the global minimum of FES reduced in an acidic environment but also the difference between the free energy of Doxorubicin as being adsorbed on poly(l-histidine) compared to when being freely dissolved in the aqueous medium show a dramatic reduction. MD simulations showed that functionalization of carbon nanotube with poly(l-histidine) groups has no detriment effect in the adsorption of Doxorubicin. The L-J interaction between Doxorubicin and carrier at the equilibrium states reached around -600 kJ/mol, both for the pristine and functionalized carbon nanotube. The coulombic interactions for both complexes were negligible in the neutral environment. At the acidic environment, the L-J interactions retained the same values as the neutral, while the coulombic interactions showed positive values, which suggested its participation in the detachments. At the vicinity of the membrane, the complexes retain their integrity both in neutral and acidic environments. In the present work, we performed metadynamics simulation to investigate the effects of poly(l-histidine) on the adsorption capacity of the carbon nanotubes, and explore the adsorption/desorption processed of Doxorubicin on pristine and poly(l-histidine)-grafted carbon nanotube. The resulted complexes were then subjected to interact with the POPC membrane model in both acidic and neutral environments via molecular dynamic simulations. The results provided here will hopefully help in a better understanding of future drug delivery systems and be helpful in designing more efficient and smart drug delivery systems.

Surface functionalization of boron nitride nanosheet with folic acid: Toward an enhancement in Doxorubicin anticancer drug loading performance.

Loading of the Doxorubicin (DOX) as an anticancer drug molecule on boron nitride (BN) nanosheets with different sizes, in the presence and absence of Folic Acid (FA) functional groups, are investigated using molecular dynamic simulations. The obtained results from these investigations revealed that the drug molecules are spontaneously adsorbed the carriers and form stable complexes. It is also shown that an increase the nanosheet leads to an enhancement in its capacity to adsorb the drugs. Furthermore, the conjugation of BN with the FA group not only improves the BN efficiency for the drug adsorption but also helps the drug-carrier complex to target the cancerous cells. Evaluation of interaction energies reveals that L-J interaction plays an essential role in the adsorption of the drug molecules on the BN. The radial distribution function (RDF) shows that the highest drug position probability is around 0.6 nm away from the BN surface. Atomic RDF analysis is in line with the interaction energy analysis and proved that π-π stacking contributes the most to this process. Hydrogen bond (HB) analysis also shows that, although limited, the columbic interaction can be helpful in the adsorption process. Moreover, the free energy (FE) surface is explored for a system containing a BN nanosheet, an FA group, and a DOX molecule through metadynamics simulations. The obtained results reveal that the lowest FE point located in coordinations d1 = 0.70 nm and d2 = 0.84 nm, and energetically reached -280.42 kJ/mol. It can be concluded from the FE calculations that while the FA is stuck on the substrate, DOX faces difficulty in the way it be adsorbed. In return, it will be hard for the molecule to be released from the BN surface through desorption processes in neutral pH because it faces an energy barrier with a height of ∼100 kJ/mol at 1.6 nm.

Molecular interpretation of the carbon nitride performance as a template for the transport of anti-cancer drug into the biological membrane.

Evaluation of interaction mechanism between 2-dimensional (2D) nanomaterials and cell membranes is a critical issue in providing guidelines for biomedical applications. Recent progress in computer-aided molecular design tools, especially molecular dynamics (MD) simulation, afford a cost-effective approach to achieving this goal. In this work, based on this hypothesis, by utilizing theoretical methods including MD simulation and free energy calculations, a process is evaluated in which the Doxorubicin (DOX)-loaded onto carbon nitride (CN) nanosheet faced with bilayer membrane. It should be mentioned that to achieve an efficient CN-based drug delivery system (DDS), in the first place, the intermolecular interaction between the carrier and DOX is investigated. The obtained results show that the DOX prefers a parallel orientation with respect to the CN surface via the formation of π-π stacking and H-bond interactions. Furthermore, the adsorption energy value between the drug and the carrier is evaluated at about - 312 kJ/mol. Moreover, the investigation of the interaction between the CN-DOX complex and the membrane reveals that due to the presence of polar heads in the lipid bilayer, the contribution of electrostatic energy is higher than the van der Waals energy. The global minimum in free energy surface of the DDS is located between the head groups of the cell membrane. Overall, it can be concluded that the CN nanosheet is a suitable candidate for transfer and stabilize DOX on the membrane.

Assessment of the effect of external and internal triggers on adsorption and release of paclitaxel from the PEI functionalized silicene nanosheet: A molecular dynamic simulation.

In order to examine the adsorption mechanisms of paclitaxel (PTX) on silicene nanosheet (SNS) molecular dynamics (MD) simulations are carried out. The MD outcomes show that the adsorption of PTX on the pristine SNS is exothermic and spontaneous. The interaction between the PTX molecule and the pristine SNS is mainly due to the formation of π-π interactions through their aromatic rings, which are supplemented by X-π (X = N-H, C-H, and CO) interactions. Upon functionalization of SNS by Polyethylenimine (PEI), drug molecules prefer to bind to the nanocarrier instead of the polymer. In the functionalized SNS (f-SNS), the binding energy of the drug with the nanocarrier becomes stronger in comparison to the SNS case (Eads: -2468.91 vs -840.95 kJ/mol). At the acidic condition, protonation of drug and PEI cause that the interaction between PTX and the nanocarrier become weaker and drug molecules could release from the nanocarrier surface. Finally, two f-SNS and protonated f-SNS (f-pSNS) systems are induced by the electric field (EF). Evaluation of the dynamic properties of these systems (with strengths 0.5 and 1 V/nm) shows that the electric field could be acted as a stimulus for drug release from nanocarriers. The obtained results from this study provide valuable information about the loading/release mechanisms of PTX on/from the SNS surface.

Molecular insights into the loading and dynamics of anticancer drugs on silicene and folic acid-conjugated silicene nanosheets: DFT calculation and MD simulation.

The adsorption behavior of Anastrozole (ANA) and Melphalan (MEL) anticancer drugs on the surface of silicene nanosheet (SNS) and functionalized SNS with folic acid (FA-SNS) is investigated and compared using the density functional theory (DFT) and molecular dynamics (MD) simulation. The DFT calculation is performed at the M06-2X/6-31G** level to characterize the optimized geometry properties of the designed complexes. The calculated adsorption energies are in the range from -65.59 to -144.23 kJ/mol, indicating the drug absorption on the surface of SNS and FA-SNS is exergonic. The π-π interaction between the drugs and SNS surface is the main driving force in the formation of drug-carriers complexes. The quantum theory of atoms in molecule (QTAIM) results reveal that the interaction of SNS and FA-SNS with both drugs has a non-covalent nature. The natural bond orbital (NBO) analysis shows that the charge is transferred from the drug molecules to carrier in all of the investigated complexes. Furthermore, MD simulations reveal that the contribution of van der Waals energy in drug-carrier interactions is more than electrostatic energy. Also, the obtained results demonstrate that the movement of drug molecules toward the carriers is spontaneous. Our study provides insights into the drug delivery capability of SNS and FA-SNS for the delivery of two drugs (ANA and MEL).Communicated by Ramaswamy H. Sarma.

Conjugation of a smart polymer to doxorubicin through a pH-responsive bond for targeted drug delivery and improving drug loading on graphene oxide.

Polymeric nanoparticles have emerged as efficient carriers for anticancer drug delivery because they can improve the solubility of hydrophobic drugs and also can increase the bio-distribution of drugs throughout the bloodstream. In this work, a computational study is performed on a set of new pH-sensitive polymer-drug compounds based on an intelligent polymer called poly(ß-malic acid) (PMLA). The molecular dynamics (MD) simulation is used to explore the adsorption and dynamic properties of PMLA-doxorubicin (PMLA-DOX) interaction with the graphene oxide (GOX) surface in acidic and neutral environments. The PMLA is bonded to DOX through an amide bond (PMLA-ami-DOX) and a hydrazone bond (PMLA-hz-DOX) and their adsorption behavior is compared with free DOX. Our results confirm that the polymer-drug prodrug shows unique properties. Analysis of the adsorption behavior reveals that this process is spontaneous and the most stable complex with a binding energy of -1210.262 kJ mol-1 is the GOX/PMLA-hz-DOX complex at normal pH. On the other hand, this system has a great sensitivity to pH so that in an acidic environment, its interaction with GOX became weaker while such behavior is not observed for the PMLA-ami-DOX complex. The results obtained from this study provide accurate information about the interaction of the polymer-drug compounds and nanocarriers at the atomic level, which can be useful in the design of smart drug delivery systems.

Probing the effect of polyethene glycol on the adsorption mechanisms of Gem on the hexagonal boron nitride as a highly efficient polymer-based drug delivery system: DFT, classical MD and Well-tempered Metadynamics simulations.

The stability of Gemcitabine (Gem) anticancer drug on the hexagonal boron nitride (h-BN) and functionalized h-BN with polyethylene glycol (PEG-h-BN) as drug delivery carriers (DDSs) is investigated. The density functional theory (DFT) calculations, molecular dynamics (MD) simulation and Metadynamics simulations are used to study the nature of h-BN-Gem interactions as well as the role of PEG group to increase the efficiency of the DDS. The results of DFT calculations reveal that the drug physisorbed on the h-BN surface through the formation of π-π stacking with an adsorption energy range -15.08 kJ/mol to -90.74 kJ/mol. Moreover, the obtained results show that the grafting the PEG group to h-BN cause to π-π stacking is reinforced by the formation of strong HBs and leads to increase adsorption energy about 20%. There is a good agreement between DFT calculation and MD simulation results. Also, The MD simulations demonstrate in adsorption of the drug on the carriers, the contribution of van der Waals energy is more than the electrostatic energy. The well-tempered metadynamics simulations are performed to find the free energy surface (FES) of the studied systems. The FES for the Gem/h-BN and Gem/PEG-h-BN interfaces show the global minimum at around 3.0-6.0 Å and 1.2 Å, respectively. The orientational analysis proves that the global minimum can be related to the formation of π-π stacking and HB interaction.

Designing a high-performance smart drug delivery system for the synergetic co-absorption of DOX and EGCG on ZIF-8.

Due to the extreme pore volume and valuable surface area, zeolitic imidazole frameworks (ZIFs) are promising vehicles that enhance the delivery of therapeutic agents to tissues. Furthermore, these nanoporous materials have high stability in the pH and temperature of the surrounding healthy cells (37 °C and pH = 7) and an exotic potential to deform in carcinogenic environment (T > 37 °C and pH ∼ 5.5), which make them perfect smart drug delivery vehicle candidates. In this work, a series of molecular dynamics (MD) and metadynamics simulations have been performed to gain molecular insight into the mechanisms involved in the process of co-loading of doxorubicin (DOX) and EpiGalloCatechin-3 Gallate (EGCG) on ZIF-8, which form a smart drug delivery system (SDDS). The obtained results revealed that DOX was adsorbed on the carrier mostly through electrostatic interactions (E coul = ∼-1200 kJ mol-1, E tot = -1700 kJ mol-1), and EGCG was stacked on ZIF-8 mainly via van der Waals interactions (E L-J = ∼-600 kJ mol-1, E tot = ∼-1200 kJ mol-1). It is worth mentioning that the drug-drug L-J interactions (E L-J = ∼500 kJ mol-1) were also important in the co-loading process. The insertion of DOX and EGCG as additive agents to the initial ZIF-8/EGCG and ZIF-8/DOX systems led to the enhancement of the drug-carrier pair interactions to about ∼-2300 kJ mol-1 and ∼-2000 kJ mol-1, respectively. This finding implied that the drug-drug interactions had a complementary role in the development of SDDS via ZIF-8. From the metadynamics simulation, it was found that the geometry of the drugs is a determining factor in an efficient co-loading SDDS.

Enhance the efficiency of 5-fluorouracil targeted delivery by using a prodrug approach as a novel strategy for prolonged circulation time and improved permeation.

Due to the toxicity and resistance to treatment with anticancer drugs, various methods are used to improve their efficacy in cancer treatment. In this present study, in order to overcome the limitation of 5-Fluorouracil (5-FU), prodrug strategy has been pursued with using density functional theory (DFT) and molecular dynamics simulation (MDs). The main objective of this study is to examine the mechanisms of drug release from its prodrug form by using the intrinsic reaction coordinate (IRC) calculations. The reaction mechanisms of 5-FU prodrug (EMC-5-FU) in the presence of lactic acid (LA) and water molecule were theoretically studied. The IRC calculations were carried out at the M06-2X/6-311G** level in the aqueous phase through the mechanism of ester hydrolysis to obtain energies, the geometry optimization of all stationary points along the potential energy surfaces (PES), and also to determine the harmonic vibrational frequencies. The results herein presented suggest that three reaction pathways and transition states TS1 to TS2 are involved along the calculated potential energy surface. We found that the drug molecule is released in the third step and this occurs by separation CH2O group in the presence of water molecule with the highest energy barrier about 25.9 kcal/mol. Since the carbon nanotubes (CNTs) can act as drug delivery vehicles and deliver anticancer drugs directly to the target cells. Therefore in DFT section, the interaction mechanism of CNTs with 5-FU prodrug is studied by means of DFT method. The atoms in molecules (AIM) and the non-covalent interactions (NCI) between the CNTs and prodrug are used in order to examine the strength and type of interaction between them. The result of negative binding energy values of CNT-prodrug interaction show the stability of these complexes. Our theoretical results show that the more favorable interaction occurs when the prodrug is located inside the carbon nanotube. Furthermore, for design and development of intracellular drug delivery systems, steered molecular dynamics (SMD) simulations was used to investigate the possibility of encapsulated prodrug-CNT penetration through a (1-palmitoyl-2-oleoyl phosphatidylcholine) POPC lipid bilayer. For this purpose, the forces of penetration and the free energies of rupture of POPC bilayer with a Prodrug-CNT were studied. Our simulation results show that encapsulated prodrug-carbon nanotube does not permanently destroy the POPC membrane structure.

Using molecular dynamics simulation to explore the binding of the three potent anticancer drugs sorafenib, streptozotocin, and sunitinib to functionalized carbon nanotubes.

The adsorption of the anticancer drugs sorafenib (SF), streptozotocin (STZ), and sunitinib (STB) on pristine and functionalized carbon nanotubes (FCNTs, functionalized with valine or phenylalanine moieties) was investigated using molecular dynamics simulation. Descriptors such as the van der Waals (vdW) energy, the number of hydrogen bonds, and the radial distribution function were considered. It was found that the type of functional group on the nanotube is a key influence on the vdW interaction energy between a drug molecule and a nanotube. In addition, the positions of the functional groups on a nanotube are a key influence on the adsorption of drug molecules on its surface. Our study indicated that the adsorption of STZ on CNT/FCNTs involves a partial π-π interaction and hydrogen bonding, whereas SF and STB are adsorbed on CNT/FCNTs through π-π stacking and hydrogen bonding. Our results suggest that altering the functionalization of the nanotube surface can affect the drug-nanotube interaction. The results reported here should aid attempts to optimize the design of novel CNT-based drug carriers.

Stabilization of d-lactate dehydrogenase diagnostic enzyme via immobilization on pristine and carboxyl-functionalized carbon nanotubes, a combined experimental and molecular dynamics simulation study.

The most important mode of enzyme inactivation is thermal inactivation. Immobilization technology is an efficient approach to elongate the life-time of enzymes. d-lactate dehydrogenase (D-LDH) was stabilized at high temperatures with immobilization on CNT and fCNT. The kinetic and thermodynamic parameters, optimum temperature and pH, and the intrinsic fluorescence of free and immobilized enzymes were examined in the present study. Also, an attempt was made to investigate the effect of CNT and fCNT on the adsorption and conformation of d-lactate dehydrogenase using molecular dynamics (MD) simulations. In comparison with free enzyme, the immobilized enzyme displayed an improved stability at high temperatures and, therefore, the immobilized enzyme is suitable for use in the industry because most reactions in the industry happen at high temperatures. Results of the present study showed that the adsorption of enzyme on CNT is mediated through the van der Waals and π-π stacking interactions, whereas in the adsorption of enzyme on fCNT in addition to hydrophobic interactions, the hydrogen bonding between enzyme and functional groups of fCNT is involved. Moreover, RMSD, RMSF and secondary structure analysis indicate that the fCNT protects the conformation of enzyme more than CNT. Therefore, D-LDH can be efficiently immobilized upon the fCNT compared to the pristine CNT.