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. 2022 Sep 12;7(38):33808–33820. doi: 10.1021/acsomega.2c02347

Density Functional Theory Interaction Study of a Polyethylene Glycol-Based Nanocomposite with Cephalexin Drug for the Elimination of Wound Infection

Oluwasegun Chijioke Adekoya †, Gbolahan Joseph Adekoya †,∥, Rotimi Emmanuel Sadiku †, Yskandar Hamam ‡,§, Suprakas Sinha Ray ∥,⊥,*
PMCID: PMC9520710  PMID: 36188269

Abstract

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In this paper, density functional theory (DFT) simulations are used to evaluate the possible use of a graphene oxide-based poly(ethylene glycol) (GO/PEG) nanocomposite as a drug delivery substrate for cephalexin (CEX), an antibiotic drug employed to treat wound infection. First, the stable configuration of the PEGylated system was generated with a binding energy of −25.67 kcal/mol at 1.62 Å through Monte Carlo simulation and DFT calculation for a favorable adsorption site. The most stable configuration shows that PEG interacts with GO through hydrogen bonding of the oxygen atom on the hydroxyl group of PEG with the hydrogen atom of the carboxylic group on GO. Similarly, for the interaction of the CEX drug with the GO/PEG nanocomposite excipient system, the adsorption energies are computed after determining the optimal and thermodynamically favorable configuration. The nitrogen atom from the amine group of the drug binds with a hydrogen atom from the carboxylic group of the GO/PEG nanocomposite at 1.75 Å, with an adsorption energy of −36.17 kcal/mol, in the most stable drug–excipient system. Drug release for tissue regeneration at the predicted target cell is more rapid in moist conditions than in the gas phase. The solubility of the suggested drug in the aqueous media around the open wound is shown by the magnitude of the predicted solvation energy. The findings from this study theoretically validate the potential use of a GO/PEG nanocomposite for wound treatment application as a drug carrier for sustained release of the CEX drug.

1. Introduction

The rising prevalence of impaired wound healing among the population and the need for cost-effective wound dressings contribute to global concerns for wound care.1−3 Bacterial infections of wounds, burns, diabetes, and ulcers on the skin have become a severe public health concern. Inflammation produced by infections (microbes), tissue necrosis, immunological responses, and foreign substances has traditionally been treated by reducing, blocking, or inhibiting proinflammatory mediators.4−6

Wounds are categorized as acute or chronic based on their healing process. Acute wounds heal in around 2–3 months, depending on the depth and extent of the skin damage. Chronic wounds that remain open longer due to a weakened immune system or an underlying medical condition might expose patients to more bacteria.7−13 Moreover, wound environments present several significant challenges for delivering antimicrobial agents to the locally infected site. The inability to achieve equilibrium in the inflammatory cascade, logistical issues, pain, and heterogeneity of the wound environment contribute to the clinical challenges. Wound healing often requires treatment with antibiotics.14 To optimize and improve the usage of currently available antibiotics, antibiotics’ drug delivery systems (DDSs) have attracted much attention.15 Example of antibiotic drugs used in delivery systems for wound healing is cephalexin (CEX).10 CEX, commonly known as beta-lactam antibiotic, is a first-generation cephalosporin that works against Gram-positive and Gram-negative bacteria by interfering with cell wall development. CEX has been used to treat urinary tract infections, bone and joint infections, middle ear infections, and skin infections. It is also effective against throat infections, pneumonia, and bacterial endocarditis.13,16−18

Wound dressing protects the skin wound and aids in the recovery of dermal and epidermal tissues throughout the wound healing process.1,7,12,19−25 Polymeric wound dressings–drug nanocarriers are a cost-effective and intelligent method that may be employed in DDS design.26 Consequently, several investigations have used PEG hydrogels, blends, and composites to administer antibiotics for wound healing.27−29 For instance, Ilhan et al.30 used 3D printing technology to produce and analyze Satureja cuneifolia plant extract (SC)-blended sodium alginate (SA)/PEG scaffolds as a diabetic wound dressing material. Mazloom-Jalali and colleagues31 designed and fabricated biocompatible nanocomposite films based on chitosan and PEG polymers containing CEX antibiotic drug and zeolitic imidazolate framework-8 (ZIF-8) nanoparticles (NPs) to develop wound dressing materials capable of controlled drug release. Meanwhile, Jafari and his colleagues32 developed a hydrogel-based treatment to speed up full-thickness wound healing. By using direct-writing melt electrospinning, fiber mats of poly(ε-caprolactone) (PCL), PEG, and Ciprofloxacin (CPFX) with various geometric configurations were effectively manufactured, and the releasing behavior of CPFX was examined in vitro by He et al.33 Similarly, the PCL/PEG diacrylate (PEGDA)/copper oxide-exchange zeolite (Z-CuO) composites synthesized by the semi-interpenetrating network were explored by Mahdis and colleagues.34 Haryanto and colleagues employed an electron beam irradiation-based crosslinking technique to generate polyethylene oxide-PEG dimetacrylate for wound dressing applications.35

Similarly, the biocompatibility and antibacterial characteristics of graphene-based bandages have sparked interest in wound healing.36 Both Gram-positive and Gram-negative bacteria were shown to be more susceptible to GO.37−39 Nanotubes, nanofibers, and nanorods made of graphene offer huge therapeutic potential in sectors including skin, bone, neural, skeletal muscle, cartilage, adipose tissue engineering, and regeneration. Membranes using graphene oxide (GO) have a high-water vapor transfer rate, as well as excellent water and exudate absorption, mechanical strength, and cytocompatibility.40 Furthermore, the high dispersibility and hydrophilicity of GO improve tensile strength by creating hydrogen bonds between the filler and matrix in composite materials, which is a significant attribute for wound dressing materials.41−43

The interfacial contact between the polymer and the nanofiller is important in determining the characteristics of nanocomposites. Owing to the presence of functional groups, it is predicted that polar polymers, such as PEG, will display greater interfacial bonding with GO either through covalent or noncovalent interactions (NCIs).44 By extension, they will exhibit good interaction with CEX. Likewise, regulating the interfacial contact is critical for improving nanofiller dispersion. The latter is especially important for graphene-like nanofillers, which can benefit from graphene’s enormous surface area to improve the performance of polymer nanocomposites and the delivery of drugs. Several studies have proven the relevance of interfacial interactions in drug delivery.45 For instance, Katuwavila and co-workers46 recently investigated the sustained release efficacy of the GO/PEG nanocarrier system for the delivery of the CEX drug against Staphylococcus aureus and Bacillus cereus infections. It should be noted that it is based on this experiment that this study seeks to theoretically validate the efficacy of the GO-PEG nanocomposite as a suitable vehicle for the delivery of CEX drugs using density functional theory (DFT) calculations.

Computational studies are regularly carried out to predict the electronic and structural features of various systems. The characteristics of doxorubicin on PEGylated GO nanocarriers, for example, were investigated using molecular dynamics.47 Similarly, DFT is a useful tool for predicting, analyzing, and explaining chemical processes.48 Farzad and colleagues49 employed DFT simulations to investigate the drug delivery potential of hexagonal boron nitride (h-BN) and PEGylated h-BN (PEG-h-BN) for the delivery of gemcitabine, an anticancer drug. The drug is covalently bound on the h-BN surface by the development of π–π stacking with an adsorption energy of −26 kcal/mol.49

Therefore, in this study, the interaction of the GO-PEG nanocomposite with the CEX drug was investigated using first-principle calculations to understand the adsorption mechanism and chemical reactivity of the excipient–drug system. The adsorption energy and adsorption distance of the drug from the nanocomposite were determined. Besides, the recovery time and quantum molecular descriptors were evaluated and analyzed in-depth with emphasis on the energy gap, chemical hardness, chemical potential, electronegativity, and electrophilicity of the complex. The behavior of the complex in the solvent phase was investigated to mimic the wet environment of an open wound. Figure 1 demonstrates the 3D structural representation of the GO, PEG, and CEX drugs under study.

Figure 1.

Figure 1

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Optimized ball and stick structural representation of GO, PEG, and the CEX drug under study. Red, blue, white, yellow, and grey balls represent oxygen, nitrogen, hydrogen, sulfur, and carbon atoms, respectively.

2. Computational Method

This study developed the nanocarrier by constructing and performing an adsorption simulation between a dimer of polyethylene glycol (PEG) and 4x4-GO. The GO was constructed with four −OH terminations and four COOH terminals around the nanosheet edges. The CEX drug molecule was also modeled, and then the structure was optimized along with the GO and PEG structures using the DMol3 module within Materials Studio 2020 software at B3LYP exchange–correlation with the DNP basis set.50 Similar to 6-31G** Gaussian basis sets, the DNP basis set has a comparable accuracy.51,52 DFT calculations were performed with long-range dispersion correction using the Grimme method.53−55 The geometry optimization convergence tolerances were set to 0.002 Ha/Å for the force, 10–5 Ha for the energy, and 0.005 for the displacement, with the electronic SCF tolerance set to 10–6 Ha (1 Ha = 27.21 eV). To accurately find the most thermodynamically favorable configuration for the drug–excipient system, an adsorption calculation was performed using Adsorption Locator module within Materials Studio 2020 software. This calculation employs the Monte Carlo method to sample various configurational spaces to predict the drug’s most stable and optimized binding location on the nanocomposite.56 In this way, the local energy minima are determined by gradually lowering the temperature of the system as the drug gets adsorbed onto the nanocomposite. Equation 1 expresses the acceptable probability of the selected configuration, where the acceptable transition of configuration m is the one with probability (ρn > ρm), and a lower probability (ρn < ρm) is extremely unlikely to be accepted.

2. 1

where ρm denotes the frequency of sampled m configurations, ρn denotes the frequency of suggested n configurations, and Pmn denotes the likelihood of a configuration transition from m to n.

Equation 2 is used to calculate the CEX drug’s adsorption energy Eb on PEGylated GO nanosheets in the gas phase, while the total energy of the system with long-range dispersion correction is obtained from eq 3.57

2. 2
2. 3

where EGO/PEG/CEX, ECEX , and EGO/PEG are the energies of the drug–excipient system, the drug molecule, and the nanocarrier, and Grimme proposed EDisp, which stands for empirical dispersion correction.

The energetic properties of the molecules, such as quantum molecular descriptors, electrostatic potential, and charge transfer (by Mulliken analysis), are evaluated from a single-point energy calculation using DMol3 module.50 The NCIs were computed using Multiwfn software,49 and visual molecular dynamics (VMD) software58 is employed to visualize the plots. Meanwhile, CASTEP program in Materials Studio 2020 is employed to calculate and analyze the infrared (IR) spectrum of the molecules. VAMP module is used to compute the UV optical spectra of the various drug–excipient complexes in both gas and aqueous phases. VAMP is a molecular orbital program that is semiempirical, and it provides crucial information such as oscillator strength and excitation energies of the molecules in the presence of visible light.

The conductor-like screening model (COSMO)59,60 of solvation developed in DMol3 code was used to investigate the impact of solvation on the stability of the intended complexes. The COSMO model is a dielectric model in which the solute molecule is encased in a molecule-shaped cavity and surrounded by a dielectric medium with a predetermined dielectric constant.61 For the solvation calculation, water solvent is employed to mimic the open wound with a dielectric constant of 78.54. The computational procedure used in this study is schematically summarized in Figure 2.

Figure 2.

Figure 2

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Schematic presentation of the computational approach as performed using Materials Studio 2020 for both gas and solvent phases.

3. Results and Discussion

3.1. Interaction of PEG/GO with CEX

To investigate the interaction of the CEX drug on the GO/PEG nanocomposite, we examined the most favorable adsorption site of the optimized drug molecule on the nanocarrier by performing an adsorption calculation using Adsorption Locator in Materials Studio 2020. However, before investigating the interaction, the structure of the GO/PEG nanocarrier was modeled by running an adsorption calculation between the optimized GO nanosheet and the optimized PEG dimer. DMol3 was used to carry out geometry optimization on the structures of the drug and excipient system before adsorption calculation. Figure 3 shows the optimized configuration of the GO/PEG-CEX complex in a gas and solvent environment. From the most stable configuration, the calculated adsorption energy of the CEX drug on the nanocomposite in a gaseous environment is −36.17 kcal/mol (Table 1). This result is slightly higher than the adsorption value obtained in a moist environment (−26.38). The shortest distance between the drug and the polymer-based excipient is 1.75 Å when in the gas phase. However, the distance reduces to 1.65 Å in a solvent. The drug adsorbs preferentially to the edge of the GO sheet owing to the strong hydrogen bonding between the hydrogen atom of the carboxylic functional group on the GO sheet and the nitrogen atom of the amine group on the CEX drug molecule. Moreover, the drug experiences strong interaction with the GO/PEG, predominantly through an established hydrogen bonding at three different sites, as shown in Figure 3. Similarly, PEG interacts with GO through hydrogen bonding of the oxygen atom on the hydroxyl group of PEG with the hydrogen atom of the carboxylic group on GO with an adsorption energy of −25.67 kcal/mol (Table 1). However, the drug interacted with the PEG through repulsive C–H...C, with CEX interacting favorably only with the GO surface through a H-bond. It was observed that while the shortest interaction distance reduces slightly, the PEG molecule experiences orientational reconfiguration at a slight tilt angle, which accounts for the overall reduction in the total adsorption energy of the system. This led to the decrease between the C–H...C of PEG and CEX, as shown in Figure 3. The negative value of the adsorption energy indicates that the interaction of CEX with the nanocomposite is exothermic, and the resulting complex is energetically favorable. When the adsorption of the drug molecule is compared to the adsorption energy of the PEG to the GO sheet, the CEX drug displayed stronger interaction with the GO sheet (Figure S1, Supporting Information).

Figure 3.

Figure 3

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Optimized 3D structures of the adsorption of the GO/PEG-CEX complex (a) gas phase and (b) water solvent phase. Oxygen, nitrogen, hydrogen, sulfur, and carbon atoms are represented by red, blue, white, yellow, and grey balls, respectively.

Table 1. Adsorption and CEX Drug Release Properties of the Nanocomposite and the Complexes.

structure configuration Eb (kcal/mol) D (Å) τ (ms)
GO–PEG (gas) –25.67 1.72  
GO/PEG–CEX (gas) –36.17 1.75 3.26 × 1011
GO/PEG/CEX (water) –26.38 1.65 2.17 × 104
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The reduced density gradient (RDG)62 (Equation 4) analysis is a valuable method for determining the type of intermolecular interactions between the medication and the carrier molecules.62 In the area with low electron density and low RDG, NCIs can be seen. The intensity of the interaction is related to electron density ρ(r) and the sign of the electron density Hessian matrix’s second eigenvalue (sign λ2). Thus, this approach may be used to describe interaction zones [the real space function sign of λ2(r)ρ(r)], as well as discriminate between different types of interactions. The strong attractive interactions [Signλ2(r)ρ(r) < 0], such as hydrogen bond, are depicted in blue, and the lesser attractive interactions [Signλ2(r)ρ(r) ≈ 0], such as van der Waal (vdW) attraction are represented in green, and the strong repulsive interactions [Signλ2(r)ρ(r) > 0], such as the steric effect, are represented in red. The RDG-based NCI isosurface plots of the optimized structure of GO, the most stable configurations of the GO/PEG nanocomposite, and the GO/PEG-CEX complex are displayed in Figure 4.

3.1. 4

Figure 4.

Figure 4

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RDG isosurface map for the prediction of NCIs of (a) GO, (b) GO/PEG, and (c) GO/PEG–CEX. The value of the isovalue has been set to 0.5. Filling color according to the color bar represents the value of Sign(λ2)ρ in the surfaces.

The strong repulsive force (steric effect) generated within the carbon ring dominates the GO structure, resulting in a noticeable undulation in the optimum structure, as seen in Figure 4a. Meanwhile, the configuration of the COOH group on the edge of the GO sheet display van der Waal’s interaction with the hydrogen atom at the edge of the sheet. The adsorption of PEG onto the GO sheet is predominantly through the hydrogen bonding between the terminal oxygen atom of the PEG and the hydrogen atom of the COOH group on the edge of the GO sheet (Figure 4b). After the adsorption of CEX, significant alterations in the general properties of the pristine nanocarrier graph were found in the [Signλ2(r)ρ(r) < 0] region (i.e., strong attraction). Also, the RDG isosurface plot of the GO/PEG–CEX complex shows that strong hydrogen bonding is responsible for the binding of the drug to the nanocarrier at three different binding sites. As a result, CEX had a significant interaction with the carrier.

3.2. Release Mechanism of CEX from GO/PEG

This section studied how the CEX drug molecule was released in the specified location from our investigated polymer-based carrier. For our most stable configuration, we examined the adsorption energy in both a gas and solvent environment. Water was chosen as the medium because it closely matched the in vitro release profile of GO–PEG–CEF in PBS solution at pH 7.4.46 The following equation relates the CEX drug’s adsorption energy on the GO/PEG nanocomposite to the nanosheet’s recovery time.

3.2. 5

where T is the temperature, k is the Boltzmann’s constant (∼1.99 × 10–3 kcal/mol·K), and v0 is the frequency of the attempt. If UV light is employed for this purpose, the value v0 (s–1) at room temperature is determined to be 1012 s–1.63−67 The adsorption energy of the drug on the carrier is proportional to the recovery time of the GO/PEG nanocomposite, as shown by the previous equation. As reported above, because the adsorption energy of the most stable complex is strong enough to prevent the drug adsorption on the nanocomposite sheet from immediate recovery, the recovery duration at room temperature is likewise long, as indicated in Table 1. This is in accordance with the report of ref (46) in which GO/PEG exhibited sustained release of CEX for the treatment of the wound. This high value is appropriate only for sustained release of the drug at the target site. For the solvent environment, in the most stable configuration, the adsorption distance of the drug from the carrier decreases to 1.65 Å, and the predicted adsorption energy decreases to −26.38 kcal/mol, which leads to a shorter recovery time. The calculated recovery time for the drug to be released in an open wound is 2.17 × 104 ms in moist environments.

3.3. Electronic Properties and Quantum Chemical Descriptors

A computational technique in which DFT has been proven to be an efficient tool may be used to forecast a molecule’s chemical reactivity. The energy of frontier molecular orbitals, such as the lowest unoccupied molecular orbital (LUMO) and the highest occupied molecular orbital (HOMO), can be used to calculate chemical descriptors at the atomic level in order to investigate a molecule’s optoelectronic capabilities. The HOMO and LUMO orbitals of optimized CEX, GO/PEG, and GO/PEG/CEX structures are shown in Figure 5. The HOMO orbital of CEX is predominantly focused on (−C–C−) and (−C=C−) of the phenyl group and (−N–H) of the amino group according to the frontier molecular orbital (FMO) study, whereas the LUMO orbital is found on (−C–C−), (−C–N−), and (−C=O). The HOMO and LUMO orbitals are predominantly located on the (−C=C−) of the GO sheet for the nanocarrier and complex.

Figure 5.

Figure 5

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HOMO and LUMO orbitals of optimized structures of (a) CEX, (b) GO/PEG, and (c) GO/PEG/CEX. The isosurface value is ±0.03e/Å3.

The excitation energy associated with a molecule determines its hardness and softness. Generally, hard molecules have a large energy gap (ΔE), while soft molecules have a small energy gap and are more reactive. Owing to the wide energy gap associated with hard molecules, modifying their electron concentrations is challenging. The energetic properties of the drug, nanocarrier, and complexes are presented in Table 2. The energy gap (Eg), which is the difference between the energy of the HOMO (the ionization potential) and energy of the LUMO orbitals (electron affinity), and the percentage of changes (% ΔEg) of the molecules are calculated as follows.

3.3. 6
3.3. 7

where Eg(GO/PEG) and Eg(GO/PEG/CEX) are the energy gap of the nanocarrier sheet before and after adsorption of the CEX drug, respectively.68

Table 2. Energetic Properties of the Drug, Nanocarrier, and Complexes.

structure configuration ELUMO (eV) EHOMO (eV) Eg (eV) ΔEg (%) η (eV) μ (eV) s (eV) ω (eV) ECT
Gas
PEG 1.42 –7.18 8.6   4.3 –2.88 0.23 17.83  
CEX –1.61 –6.60 4.99   2.495 –4.105 0.40 21.02  
GO –3.53 –5.03 1.5   0.75 –4.28 1.33 6.87  
GO/PEG –3.48 –5.00 1.52   0.76 –4.24 1.32 6.83  
GO/PEG/CEX –3.45 –4.93 1.48 2.63 0.74 –4.19 1.35 6.50 3.93
Water
PEG 1.68 –7.29 8.97   4.485 –2.805 0.22 17.64  
CEX –1.63 –6.68 5.05   2.525 –4.155 0.40 21.80  
GO –3.41 –4.93 1.52   0.76 –4.17 1.32 6.61  
GO/PEG –3.39 –4.91 1.52   0.76 –4.15 1.32 6.54  
GO/PEG/CEX –3.45 –4.97 1.52 0.43 0.76 –4.21 1.32 6.74 3.89
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Except for the nanocarrier, the HOMO and LUMO energies of the drug and complex in water are lower than in the gas phase. In a moist medium, the interaction of the medication with the nanocarrier does not affect the carrier’s energy gap. However, as the energy gap narrows in the gas phase, the complex’s reactivity increases slightly. As a result, we can conclude that the drug and the carrier interact in an electronically harmless manner and that the nanocarrier has no substantial effect on the medicine’s qualities.

Besides, the Eg is a useful measure for determining a nanostructure’s sensitivity to various chemical agents on several occasions.69 The equation below relates electrical conductivity (α) to Eg.

3.3. 8

where A (electrons/m3 K3/2) is a constant, and k is the Boltzmann’s constant. Many articles have shown that the results of eq 8 accord well with those of experimental studies.67 This equation states that as the Eg decreases, the electrical conductivity increases exponentially.69 Consequently, the conductivity that correlates with the complex’s energy gap is higher in the gas phase than in the wet phase. Also, it is consistent with higher reactivity of the structure in the gas phase, as concluded above.

We compute the electrophilicity-based charge transfer to determine the direction of charge transfer (ECT). The ECT approach is useful for determining if a complex’s interacting molecules are electron donors or acceptors (nucleophilic or electrophilic behavior). The difference between ΔNmax values of interacting molecules is defined as ECT (eq 9). Equations 10 and 11 can be used to calculate the maximum electronic charge ΔNmax that a molecule can receive from the environment. Charges will be transferred from the drug to the carrier if ECT is more than zero. Charges will tend to flow from the nanocarrier to the drug molecule if ECT is less than zero.70,71 According to eq 12, electronegativity (χ) refers to a molecule’s ability to attract electrons. Besides, we computed the chemical hardness (η) and softness (s)72,73 (calculated from eqs 13 and 14), which measures the charge transfer and the chemical reactivity of a molecule. Then, the chemical potential (μ), which is obtained from eq 15, determines the evasion affinity of a molecule from equilibrium. Finally, the electrophilicity index (ω) is a parameter in which a greater value of ω means higher electrophilic power of a molecule (evaluated from eqs 16 and 17) (Table 2).

3.3. 9
3.3. 10
3.3. 11
3.3. 12
3.3. 13
3.3. 14
3.3. 15
3.3. 16
3.3. 17

For CEX and GO/PEG, the calculated ΔNmax values were 0.58 and 0.73, respectively. Positive ECT values reveal charge flow from CEX to GO/PEG for the interaction of CEX with GO/PEG in both moist and dry environments.

Researchers often employ the COSMO model to find viable solvents for therapeutic compounds, and the predicted solubility results have been shown to be in good agreement with experimental results.74−76 Klamt and Schuurmann were the first to present the COSMO, a continuum solvation model based on quantum chemistry with a remarkable ability to forecast chemical and physical attributes in solvent media.77 The solute molecule in COSMO symbolizes a cavity within the solvent’s dielectric continuum with a particular permittivity. The solute’s charge distribution polarizes the solvent’s dielectric medium. The dielectric medium produces screening charges on the cavity surface in response to charge distribution. The solute molecule is assumed to have infinite permittivity in COSMO calculations, in which case the screening charges are located on the molecular surface. One must supply the electrostatic charge and its position in space in order to continue with the quantum mechanics computation. Some cavity and surface construction algorithms are used to pinpoint the positions of the surface charges.

Owing to the perfect conductor enclosing the cavity, the boundary condition of vanishing electrostatic potential on the surface allows for the determination of the screening charges. In order to get screening charges, COSMO does not require a solution to the somewhat complex boundary conditions for a dielectric. The DFT is instead used to determine the screening charges.78 To simulate the impact of the bulk solvent environment for drug carriers, Materials Studio’s Dmol3 employed in this study is built for COSMO-based quantum chemistry computations; as such, the water COSMO potential (=78.54) is used.77,79−81

In addition, the stabilities of the drug–nanotube complexes are evaluated by the solvation energy, which is calculated according to the equation:60Esol = Esolvent – Egas, where Esol is the solvation energy, Esolvent is the total energy in water solvent, and Egas is the total energy of the system in the gas phase. The solvation energy calculated for the GO/PEG-CEX complex is −64.77 kcal/mol. This value is substantially higher than the predicted solvation (Esol) energy of the crizotinib drug on carbon nitride nanotubes (−39.13 kcal/mol).81

3.4. Electrostatic and Charge Transfer Analysis

A descriptor for identifying the best site of interaction for donor–acceptor complexes and recognizing sites of positive and negative electrostatic potentials for nucleophilic reactions and electrophilic attacks is the molecular electrostatic potential (MEP) map, which displays the electronic density in molecules. Features such as electronegativity, chemical reactivity, and dipole moment are related to total charge densities and can thus be predicted using MEP. As shown by the colors red and orange, negative electrostatic potentials with high electron density have been linked to electrophilic reactivity.71 However, the positive regions of electrostatic potential with low electron density, which are illustrated in blue and green, have been linked to nucleophilic reactivity. In contrast, the neutral zones are shown in light yellow-green color.82−84Figure 6 shows the MEP map of the (a) drug (CEX), (b) carrier (GO/PEG), and (c) GO/PEG-CEX complex with an isosurface value is ±0.016e/Å3.

Figure 6.

Figure 6

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MEP surfaces of the optimized structures of the (a) CEX, (b) GO/PEG, and (c) GO/PEG-CEX. The electron-enriched domain is depicted in blue, while the depletion of electron density is depicted in red. The isosurface value is ±0.016e/Å3.

The regions with the dominant negative potential are over the electronegative oxygen and nitrogen atoms. In contrast, the regions with the dominant positive potential are over the sulfur and hydrogen atoms, as can be seen from the MEP of the CEX molecule (Figure 6a). Similarly, the regions with the dominant negative potential in the MEP of the GO/PEG nanocomposite (Figure 6b) are over the electronegative oxygen atoms of the carboxylic functional group. In contrast, the regions with the dominant positive potential are over the carbon and hydrogen atoms. The negative potential contribution is across the electronegative oxygen, nitrogen atoms area of the CEX, and the electronegative oxygen atoms of the carboxylic functional groups of the GO/PEG for the resultant complex-GO/PEG-CEX (Figure 6c).

Mulliken population analysis has also been used to measure charge transfer between the CEX molecule and the carrier as an adsorption effect. More specifically, the charge transfer is computed before and after adsorption for each atom of the CEX molecule, namely the N, H, S, and C atoms, and then the charge difference before and after adsorption is estimated. A positive charge difference Qt(e) value indicates that charge has been transferred from the GO/PEG nanosheet to the CEX molecule, whereas a negative value indicates the opposite.

Given that the molecule of CEX binds to the GO/PEG nanosheet at the nitrogen atom of the amine group and the oxygen atom of the carboxylic group. The charge transfer for N and O of the CEX molecule in the gas and water phase was estimated and presented in Table 3. The interaction of the drug with the carrier is accompanied by charge transfer from the CEX molecule to the GO/PEG nanosheet. The net charge on CEX, GO/PEG, and PEG-CEX complexes from Mulliken charge analysis in the gas and water phases are shown in Figures S2 and S3 (Supporting Information). The Mulliken atomic charges of CEX and GO/PEG-CEX in gaseous and aqueous conditions are also shown in Tables S1 and S2 (Supporting Information).

Table 3. Charge Transfer Qt(e) of the GO/PEG-CEX Complex in the Gas and Water Phase.

  Qt(e)  
CEX atom gas water
N –0.117 –0.065
O –0.066 –0.029
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3.5. Theoretical IR and UV Spectra Analysis

Figure 7 shows the IR spectra of the most stable configuration of the CEX drug (a), carrier (GO/PEG) (b), and GO/PEG-CEX complex (c), which were computed using frequency calculations. No imaginary vibrational modes have been identified for any of the structures, indicating that all compounds are geometrically stable. The frequency of the strongest IR bands of CEX has been observed at 1871 cm–1, which corresponds with the C=O stretching modes of CEX according to the IR spectra of CEX. The frequencies of the three strongest IR bands were observed at 1811, 1198, and 3341 cm–1 in the IR spectra of the GO/PEG complex, which have been connected with the C=O,46 C–O, and −OH stretching modes of the carrier, respectively. The creation of the hydrogen bonding in the GO-PEG is validated by the −OH stretching (3341 cm–1). The IR spectra of the (a) GO and (b) PEG are reported in Figure S4 (Supporting Information).

Figure 7.

Figure 7

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IR spectra of the (a) CEX, (b) GO/PEG, and (c) GO/PEG–CEX.

The IR spectra have not altered noticeably following CEX adsorption on GO/PEG, as shown in Figure 7. However, the intensity of IR bonding in the GO/PEG-CEX complex is higher than that of the nanocarrier and CEX. The 1865 and 1203 cm–1 IR spectra of GO/PEG-CEX have been observed related to C=O and C–O stretching modes, respectively. The emergence of the peak in the 3500–3700 cm–1 range12,85 depicts the presence of −OH, which justifies the binding of CEX to the GO/PEG nanocarrier through strong hydrogen bonding.

The electronic structure of the molecule determines the ultraviolet (UV) spectrum. The UV spectra of the optimized CEX, GO/PEG, and GO/PEG–CEX structures in the gas and water solvent phase are shown in Figure 8. The electronic transition spectra of compounds were calculated theoretically utilizing the same level of theory for different media, namely water and gas, using VAMP, a semi-empirical molecular orbital computational code in Materials Studio. Table 4 shows the electronic properties of the optimized CEX, GO/PEG, and GO/PEG-CEX structures, including transition energies in eV, excitation wavelength in λmax, and oscillator strength. The high UV absorbance of nanocomposites samples was attributed to the energy of photons high enough to interact with atoms; the electron excites from a lower to higher energy state by absorbing a photon of known energy.

Figure 8.

Figure 8

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UV spectra of the optimized structures of the CEX, GO/PEG, and GO/PEG-CEX in (a) gas phase and (b) water solvent phase.

Table 4. UV Parameters for CEX, GO/PEG, and GO/PEG-CEX in Gas and Water Solvent Phases.

  energies (eV)
 excitation (λmax)
 oscillator strength (f)
species gas water gas water gas water
CEX 5.39 5.38 230.07 230.24 0.39 0.40
GO/PEG 2.07 2.08 599.47 595.31 1.71 1.74
  3.77 3.71 329.07 334.46 1.42 1.45
  4.93 4.54 251.71 273.25 1.09 0.84
GO/PEG-CEX 2.05 2.07 603.32 598.55 1.73 1.70
  3.72 3.77 333.56 329.06 1.29 1.34
  4.92 4.93 252.08 251.39 0.95 1.13
Open in a new tab

The electronic absorption of the CEX drug in the gas phase peaks at 230 nm with an oscillation strength of 0.39. This theoretical value is consistent with the λmax of CEX that has been reported at 264 nm86 and 262 nm87 in the literature. Meanwhile, the nanocarrier (GO/PEG) has the highest excitation from HOMO to LUMO, with a high oscillator strength of 1.71 at a maximum wavelength of 599 nm and electronic energy of 2.07 eV. The electronic absorption spectrum of the resultant complex (GO/PEG-CEX) is characterized by a prominent peak at an excitation wavelength of 603 nm with transition electronic energy of 2.05 eV when the drug is absorbed to the carrier. GO/PEG-CEX absorbs light with a longer wavelength than CEX.

In VAMP, the UV is also calculated using the self-consistent reaction field solvation scheme for the molecules in the aqueous phase. The carrier GO/PEG had a maximum at 595 nm in the UV spectrum. CEX has a λmax of 230 nm and a dipole moment of 0.40. The complex has a maximum wavelength of 598 nm. As a result, this finding clearly shows that the solvent influenced the optical activity of the compounds by shifting the λmax to a lower wavelength.

4. Conclusions

The adsorption behavior of CEX on PEGylated GO is studied using DFT simulations in this paper. Owing to the development of strong hydrogen bonds, the CEX molecule likes to be on the edge of the carrier in the most stable configuration of the GO/PEG–CEX medication. The drug has a higher tendency for adsorption on GO/PEG surfaces than the PEG to adsorb on the GO sheet in the most stable configuration of GO/PEG–CEX drug and GO/PEG. The presence of a moist environment enhances the release of CEX from the GO substrate with about a 27.06% reduction in adsorption energy. The adsorption energy of the drug on the carrier in a wet medium suggests sustained release of the CEX drug for wound infection treatment. In addition, the carrier is electronically less sensitive to the drug, particularly in a moist environment. Therefore, it has no substantial effect on the medicine’s properties if administered to a skin wound. In general, according to the findings, the carrier is a suitable nanovehicle for the sustained release of CEX medication for wound healing. This is due to the complex’s high reactivity, as well as its superior energetic, electrical, and adsorption properties.

Acknowledgments

G.J.A. would like to thank the National Research Foundation (grant number: 116083) of South Africa for the financial support. S.S.R. would like to thank the Department of Science and Innovation (grant no: C6ACH20) and the Council for Scientific and Industrial Research (grant no: 086ADMI) of South Africa for the financial support. GBJ would like to thank Oluwaferanmi Tiara Adekoya for her love and patience.

Supporting Information Available

The Supporting Information is available free of charge at https://pubs.acs.org/doi/10.1021/acsomega.2c02347.

  • Optimized 3D structures of the adsorption of CEX on GO; oxygen, nitrogen, hydrogen, sulfur, and carbon atoms represented by red, blue, white, yellow, and grey balls; IR spectra of GO and PEG (PDF)

Author Contributions

The manuscript was written through the contributions of all authors. O.C.A., G.J.A., and S.S.R. framed and organized the manuscript. R.E.S. and Y.M. edited and corrected.

NRF/TWAS: grant number: 116083/138768; DSI: C6ACH20; CSIR: 086ADMI.

The authors declare no competing financial interest.

Supplementary Material

ao2c02347_si_001.pdf (553.7KB, pdf)

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