Akor et al. BMC Chemistry(2024) 18:156
https://doi.org/10.1186/s13065-024-01259-3

BMC Chemistry

RESEARCH

Open Access

Surface modification of graphene
and fullerene with Sulfur (S), Selenium (Se),and Oxygen (O): DFT Simulation for enhanced
zidovudine delivery in HIV treatment
Faith O. Akor3, Godwin D. Edo3, Favour A. Nelson2, Abasifreke U. Johnson2, Solomon O. Iyam1,
Muhammad N. Abubakar4, Alpha O. Gulack3, Chioma B. Ubah1, Bassey O. Ekpong1* and Innocent Benjamin1
Abstract
HIV is one of the most threatening health conditions with a highly increasing rate, affecting millions of people
globally, and from its time of discovery until now, its potential cure cannot be explicitly defined. This challenge of
having no/low effective drugs for the subjected virus has called for serious attention in the scientific world of virus
disease therapeutics. Most of these drugs yields low effectiveness due to poor delivery; hence, there is a need fornovel engineering methods for efficient delivery. In this study, two nanomaterilas (graphene; GP, and fullerene; C60)
were modelled and investigated with sulfur (S), selenium (Se), and oxygen (O) atoms, to facilitate the delivery ofzidovudine (ZVD). This investigation was computationally investigated using the density functional theory (DFT),
calculated at B3LYP functional and Gd3bj/Def2svp level of theory. Results from the frontier molecular orbital(FMO), revealed that the GP/C60_S_ZVD complex calculated the least energy gap of 0.668 eV, thus suggestinga favourable interactions. The study of adsorption energy revealed chemisorption among all the interacting
complexes wherein GP/C60_S_ZVD complex (-1.59949 eV) was highlighted as the most interacting system, thereby
proving its potential for the delivery of ZVD. The outcome of this research urges that a combination of GP and C60
modified with chalcogen particularly, O, S, and Se can aid in facilitating the delivery of zidovudine.
Keywords Graphene/C60, Zidovudine, DFT, Drug delivery, HIV infection*Correspondence:
Bassey O. Ekpong
ekpongbassey242@gmail.com
1
Department of Microbiology, University of Calabar, Calabar, Nigeria
2
Department of Chemistry, University of Calabar, Calabar, Nigeria
3
Department of Science Laboratory Technology, University of Calabar,
Calabar, Nigeria
4
Department of Biotechnology, Moddibo Adama University of Yola, Yola,
Nigeria© The Author(s) 2024. Open Access This article is licensed under a Creative Commons Attribution-NonCommercial-NoDerivatives 4.0
International License, which permits any non-commercial use, sharing, distribution and reproduction in any medium or format, as long as you
give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if you modified thelicensed material. You do not have permission under this licence to share adapted material derived from this article or parts of it. The images orother third party material in this article are included in the article’s Creative Commons licence, unless indicated otherwise in a credit line to thematerial. If material is not included in the article’s Creative Commons licence and your intended use is not permitted by statutory regulation
or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://
creativecommons.org/licenses/by-nc-nd/4.0/.

Akor et al. BMC Chemistry(2024) 18:156

Introduction
Human immunodeficiency virus/acquired immunodeficiency syndrome (HIV/AIDS) presents a formidable
global health challenge with far-reaching implications.
This virus targets the immune system, undermining the
body’s ability to combat infections and diseases effectively. Consequently, individuals infected with HIV are
highly susceptible to infections and diseases [1, 2]. It is
indisputable that HIV is a significant health concern that
affects millions of people worldwide and a definitive curefor HIV has not yet been identified [3–8]. The challenge
has attracted significant attention in the scientific community of drug manufacturing [4]. Antiretroviral drugs,
such as zidovudine (ZDV), lamivudine, stavudine, anddideoxycytidine, have emerged as effective agents for
managing HIV infections [9–12]. However, challenges
persist in their effective delivery to the target site within
the host immune system. Issues such as limited penetration, adverse side effects, and metabolic concerns underscore the need for innovative drug delivery systems [13].
However, zidovudine, also known as azidothymidine(AZT), is a nucleoside analog reverse transcriptase inhibitor (NRTI) that plays a crucial role in the managementof human immunodeficiency virus (HIV) infection. It
was the first antiretroviral drug approved by the FDA in
1987 and remains a cornerstone of combination therapy
for HIV-1 infection [14]. The mechanism of action of zidovudine involves the inhibition of reverse transcription,a critical step in the HIV replication cycle. Zidovudine
is phosphorylated to its active metabolite, zidovudine
triphosphate, which competes with thymidine triphosphate for incorporation into viral DNA. This leads to thetermination of DNA synthesis, thereby inhibiting viral
replication [15]. Despite its efficacy, zidovudine delivery
to target HIV-infected T-cells remains a challenge. The
drug has poor bioavailability, rapid clearance, and limited
penetration into lymphoid tissues, where HIV reservoirs
exist [16].
To improve zidovudine delivery, recent advancements in nanotechnology and computational chemistry
approaches offer promising solutions to address thesechallenges [17–19]. Many studies have explored various
strategies, including developing nano formulations anddrug delivery systems. For instance, Petlin et al. (2017)
developed a zidovudine-loaded nanoparticle formulationthat demonstrated enhanced bioavailability and antiretroviral activity compared to the free drug [20]. Anotherstudy by Ilinskaya et al. (2019) designed a zidovudineconjugated nanoparticle that targeted HIV-infectedT-cells, resulting in improved drug delivery and antiHIV activity [21]. Amin and Boateng (2020) discussed
the use of ligand-targeted liposomes and nanoparticles for delivering zidovudine to HIV-infected cells[22]. Another review by Pradhan et al. (2021) on Drug

Page 2 of 15

Delivery highlighted the potential of nanotechnologybased approaches in enhancing zidovudine delivery andreducing toxicity [23]. Also, Dahmane et al. (2013), Joshy
et al. (2018), and Gupta et al. (2019) demonstrated thefeasibility and efficacy of utilizing various nanoparticles,
including chitosan, PF-68-coated alginate conjugates,
and fullerene-like nanocages for drug delivery [24–26].
Their outcome unveils the essentials of nanomaterials in
drug delivery applications. Therefore, in this research, we
focused on improving the delivery of zidovudine by engineering graphene sheet and fullerene C60 together andalso doped the fullerene structure with chalcogens suchas oxygen, selenium, and sulfur. Integrating chalcogenelements (oxygen, sulfur, and selenium) into the fullerene structure can enhance the material’s biocompatibility
and drug-loading capacity [27–29]. The chalcogen-doped
nanocomposite can exhibit a high surface area and excellent conductivity that can be a suitable platform for
drug carriers and controlled release [30–32]. This composite’s unique physicochemical properties contributeto improved drug stability, prolonged circulation time,and enhanced cellular uptake, ultimately optimizing thetherapeutic efficacy of a drug. Using fullerene C60 as a
nanovesicle can be attributed to the unique biocompatibility essential for drug delivery, as reported by Guanet al. and Lin et al. (2016 & 2017) [33, 34]. The uniqueelectronic and chemical properties of oxygen, selenium,and sulfur have garnered attention [35, 36], and theseproperties make them ideal candidates for incorporation
into fullerene structures aimed at improving the surfacefunctionality and opening paths for tailoring their interaction with biological entities as well as enabling specificrecognition and uptake by HIV-infected cells [37, 38].
The potential to deliver zidovudine (ZDV) directly to theaffected cell holds promise for maximum efficacy while
minimizing off-target effects and side effects.
Our study employed an advanced computational density functional theory approach encompassing electronic
properties studies (frontier molecular orbital, natural
bond orbital, and density of state) to elucidate the chemical reactivity and kinetic stability mechanisms between
nanocomposites and ZDV. The study also utilized topological analysis to effectively assess natural interactions
and interatomic interactions. The noncovalent interaction (NCI) and quantum of atom in molecule (QTAIM)
approaches were instrumental in obtaining these results.
To determine whether the drugs will be chemically or
physically adsorbed, an adsorption study and otherobjectives for desorption mechanism were achieved successfully via density functional theory (DFT) calculations.
Continued research in this field is essential to refine andoptimize these nanocomposites for enhanced antiretroviral drug delivery. Ultimately, this study revealedAkor et al. BMC Chemistry(2024) 18:156

promising outcomes for improving treatment plans forindividuals with HIV/AIDS.

Method
DFT approachThis computation was carried out employing first-principles density functional theory (DFT) simulations, calculated at B3LYP/D3(BJ)/Def2svp levels of theory. The
optimization of the combined graphene sheet and fullerene C60 nanomaterials doped with chalcogen groups was
performed utilizing B3LYP functional and the D3 (BJ)
dispersion correction in conjunction with the Def2svp
basis set, a choice given the need for a balanced compromise between accuracy and computational efficiency indescribing the intricate interactions within these complex nanocomposites. This method combination has
been extensively validated in previous studies [39, 40]
and is particularly well-suited for capturing the subtleties of non-covalent interactions and chemical bondingin large-scale systems, thereby providing a robust framework for elucidating the structural and electronic properties of these materials. The structural optimization andelectronic properties of GP/C60 were analysed to understand the nature of the coordination between selenium,oxygen, and sulfur dopants and the graphitic carbon
matrix, which was carried out using Gaussian 16 [41] andGaussian view 6.6.0.16 [42]. This approach was employed
to tailor accurate theoretical calculations. For proper
investigation of the electronic, structural, and topologicalproperties for effective delivery of zidovudine, an allusive
objective was carried out. The reactivity and molecularstability of the surface doped with ZVD were consideredvital for understanding the delivery dynamics; thus, frontier molecular orbital (FMO) analysis has been a powerful computational tool employed to investigate various
chemical processes, including the possibility of electrontransfer from individual doped and co-doped surfaces todrugs, by considering the energy gap obtained from thevalue of the HOMO and LUMO. The iso-surface of thefrontier molecular orbital was visualized using Chemcraft
software version 1.6 [43]. Similarly, other investigations
were carried out using Multiwfn package 3.7 [44] for thequantum theory of atom-in-molecule (QTAIM) studies,
which enabled the study of the intermolecular interactions occurring in the system, and the electronic distribution study was performed using the DOS approach alsoutilizing the Multiwfn package. Furthermore, the study ofthe non-covalent interaction (NCI) was carried out using
the visual dynamic simulation (VMD) software package
1.9.4 [45]. Furthermore, the interactions between zidovudine and GP@C60_Se, GP@C60_S, GP@C60_O, andGP@C60_O_S_Se were explored to elucidate the drugloading mechanism and release dynamics. The impact ofpH changes on drug release was pivotal in this study, andPage 3 of 15

computational simulations were conducted to elucidate
these effects. The simulations utilized density functional
theory (DFT) calculations implemented in Gaussian 16
software to predict the protonation states and electrostatic interactions of zidovudine and the GP/C60 carrier at different pH levels. This approach allowed for themodelling of how pH variations influence the solubility,
ionization, and binding affinities within the drug delivery
system. Additionally, to gain an in-depth understanding of the chemistry of 2D nanostructures, structural
studies and analyses of binding energy, vibrational stability, and UV‒vis excitation was carried out, providing
perspectives on the design and optimization of GP/C60
nanostructures for efficient and controlled therapeutic
delivery of zidovudine and advancing antiretroviral drugdelivery systems.

Results and discussion
Chemistry of 2D nanostructures
Structural studies

This research comprehensively examined the structuralproperties of a nanocomplex and its doped counterpart(see Fig. 1) as well as their interaction with zidovudine(see Fig. 2) by employing density functional theory (DFT)
to elucidate changes in bond lengths. This investigation
focused on understanding the implications of drug interactions on the potency, likely interactions, and stability of
the nano complexes, which will determine their suitability for efficient delivery [46]. The bond length, which isthe distance between the nuclei of atoms within a chemical bond, is a crucial parameter for this analysis [47]. This
study specifically explored the effects of the GP/C60_O_
ZVD nanocomplex and revealed a slight increase in thebond length before drug interaction, with minimal variations post-absorption. The differences in bond length,
which are methodically recorded in Table S1, revealed asequential change in the number of atomic nuclei in the
nanocomplexes. For instance, in the case of O96—C26,
there is a marginal difference of 0.00119 Å, O96—C25
exhibits a variation of 0.00314 Å, and C25—C49 displays a difference of 0.0006 Å. The overall change in bondlength across all atomic nuclei is approximately 0.001
Å, suggesting that the interactions do not significantly
decrease the bond lengths. Furthermore, this study was
extended to the analysis of other nanocomplexes, such as
GP/C60_O_S_Se_ZVD, GP/C60_S_ZVD, and GP/C60_
Se_ZVD. GP/C60_O_S_Se_ZVD exhibited diverse bondlengths, with Se96—C25 displaying a greater bond lengththan the other atomic pairs. Conversely, GP/C60_S_ZVD
reveals a substantial variation in bond lengths before andafter drug interactions, particularly with a 0.03 Å change
in some bonds and a lower 0.009 Å variation in carbon‒
carbon bonds. Also, GP/C60_Se_ZVD demonstrated thegreatest bond length, specifically for selenium-carbon

Akor et al. BMC Chemistry(2024) 18:156

Fig. 1 Structural representation of the investigated systems before and after interaction with ZVD

Fig. 2 3D Illustration of the drug target (zidovudine)

Page 4 of 15

Akor et al. BMC Chemistry(2024) 18:156

Page 5 of 15

bonds. However, the observed trend of decreasing bondlengths, as indicated by GP/C60_Se_ZVD > GP/C60_S_
ZVD > GP/C60_O_S_Se_ZVD > GP/C60_O_ZVD, suggests a correlation with enhanced drug delivery potency.
Because the decrease in bond length as observed acrossthe systems depicted a sensitivity behaviour and also
implies that the surfaces become more conjugated which
is vital characteristics of drug delivery systems. Therefore, these systems can be beneficial in the developmentof drug delivery system.
Vibrational stability

Vibrational analysis was carried out to determine thecomposition of the complexes in terms of the numberof functional groups present [48]. This analysis identifies specific functional groups within molecules basedon their characteristic absorption bands and this allow
us to infer the types of ligands and metal ions present in
the complex. The shifts in vibrational frequencies uponcomplex formation provide direct evidence of interactions between the metal ion and ligands thereby confirming the formation of the complex and indicating
the nature of metal-ligand bonding (e.g., coordination
bonds) [49]. Also, the intensity of absorption bands in
the IR spectrum correlates with bond strengths; stronger
bonds, such as metal-ligand bonds, typically exhibit more
intense absorption peaks. This information helps assess
the stability of the complex under various conditions[50]. Therefore, vibrational analysis through IR spectroscopy is essential for characterizing complex compositionand stability, providing crucial molecular-level information for advancing our understanding of coordination
chemistry and materials science. The frequencies arerecorded for both surfaces after their interaction with
ZVD to determine the stability of the nanocomposites.
The CH functional group is predominant and appears
in both symmetric and asymmetric patterns, as shownin Table S2. Functional groups such as OH, N3, NH, andCO are only present in the interactions due to the effectof zidovudine. For the CH symmetric functional group,
the frequencies before interaction ranged between
3423.64 cm− 1 and 3191.82 cm− 1. All the compounds
exhibited an exact peak at approximately 3191 cm− 1
except for GP/C60_O_S_Se_ZVD, which differs greatly
from the peak at 3423.64 cm− 1. After the interaction, thesymmetric CH functional group exhibited an increasein the range of 3192.60 cm− 1 to 3598.01 cm− 1. In thiscase, GP/C60_O_S_Se_ZVD decreases slightly, while
the other compounds increase. The asymmetric CH
functional group also falls in a similar range as the symmetric group, and GP/C60_O_S_Se_ZVD still shows thesame deviation. The functional group CO is recorded for
only GP/C60_O_ZVD and GP/C60_Se_ZVD because
the other two compounds did not experience vibrations
at the CO functional groups. For the surfaces, only GP/
C60_O_ZVD experiences a CO vibration since oxygen ispart of its components at both the surface and interaction levels. For GP/C60_O_ZVD, the frequency before
the interaction was recorded to be within the range of1600 cm-1. After the interaction, the CO functional frequency ranged from 1800 cm− 1 for GP/C60_O_ZVD
to 3175.77 cm− 1 for GP/C60_Se_ZVD, which is muchgreater than the normal range for the CO functionalgroup [49, 50], indicating high stability of the CO functional group of the GP/C60_Se_ZVD complexes. The N3
vibrational frequency is only recorded in GP/C60_O_
ZVD and GP/C60_Se_ZVD and falls in the range of1700 cm− 1 for both compounds.
UV‒vis excitation analysis

The major aim of this analysis was to determine thebehaviour of the complexes when the absorption of ultraviolet rays occurs at a particular wavelength. In Table 1,parameters such as the stabilization energy, excitation type, percentage transitions between the highest
occupied molecular orbital and the lowest unoccupied

Table 1 UV‒vis analysis results for all the studied systems showing the following parameters: excitation type, energy (eV), wavelength(nm), percentage contribution (%), oscillator strength (f ) and transition
SystemGP/C60_O_ZVD

Excitation type
S0-S1
S0-S2
S0-S3
GP/C60_S_ZVD
S0-S1
S0-S2
S0-S3
GP/C60_Se_ZVD
S0-S1
S0-S2
S0-S3
GP/C60_O_S_Se_ZVD S0-S1
S0-S2
S0-S3

Energy (eV)0.885
1.04041.0808
1.260
1.342
1.724
1.014
1.095
1.159
0.763
1.316
1.358

Wavelength(nm)1401.701191.75
1147.13983.77924.25719.131222.35
1132.54
1069.59
1624.60
941.92912.97

Percentage contribution (%)
329 -> 330 (149.6%)
330 -> 332 (115.1%)
330 -> 331 (140.4%)
263 -> 264 (140.7%)
263 -> 265 (140.6%)
263 -> 266 (139.3%)
342 -> 343 (164.9%)
343-> 344 (126.4%)
343-> 345 (138.8%)
278 -> 279 (139.9%)
275 -> 279 (96.1%)
278 -> 280 (97.6%)

Oscillator strength (f)0.00040.00060.00090.00110.00420.00910.00030.00020.00000.00560.01070.0024

TransitionH + 1-> L-1
H-> L + 1
H-> L
H-> L
H-> L + 1
H-> L + 2
H + 1-> L-1
H-> L
H-> L + 1
H-> L
H + 3-> L
H-> L + 1

Akor et al. BMC Chemistry(2024) 18:156

molecular orbital, and the strength of the oscillators ineach excitation type are presented. It has already been
established from the energy of photons that energy
increases with increasing frequency and decreasing
wavelength [51], which is represented by the following
equation:

E = h×v
λwhere h is Planck’s constant (h = 6.626 × 10− 34 Js− 1), v isthe speed of light (v = 3.0 × 108 ms− 1) and λ is the wavelength at which the system absorbs ultraviolet radiation[52, 53]. The interactions are discussed for three excitation types: S0-S1, S0-S2, and S0-S3. For this study, as presented in Table 1, the stabilization energy increased in thefollowing order: GP/C60_O_ZVD > GP/C60_S_ZVD > GP/
C60_Se_ZVD > GP/C60_O_S_Se_ZVD. However, a slightdifference is observed in GP@C60_O_S_Se_ZVD, where
the first excitation type S0-S1 is much lower by 0.763 eV
compared to S0-S1 of GP/C60_O_ZVD, with an energyof 0.885 eV, which is second to the former. Comparing the S0-S3 excitation type for the interactions, GP/
C60_O_S_Se_ZVD records the highest energy of 1.358 eVon the table, followed by GP/C60_Se_ZVD with an energyof 1.159 eV in the S0-S3 type. The wavelength generally
decreases from S0-S1 to S0-S3. This is due to the increasein energy in the system, as seen in the formula above. The
wavelengths are generally longer in S0-S1 and shorter in
S0-S3. For GP/C60_O_ZVD, the energy decreases between
1147.13 and 1401.7 nm, that of GP/C60_S_ZVD decreases
between 719.13 and 983.77 nm, that of GP/C60_Se_ZVD
decreases between 1069.59 and 1222.35 nm, and that of
GP/C60_O_S_Se_ZVD decreases between 912.97 and
1624.60 nm. Comparing these interactions, we see that
GP/C60_O_ZVD records the largest wavelengths andsmallest energy stabilization energy. This implies thatthe system is less stable and more reactive since its lightabsorption rates are so intense judging from its longwavelengths. The percentage contribution of each excitation type is recorded. GP/C60_O_ZVD at S0-S1 witha H + 1-> L-1 transition indicates that the absorption
occurs slightly below the HOMO and slightly above the
LUMO with a percentage of 149.6%, and at S0-S2 with a
H-> L + 1 transition occurs exactly between the HOMO
and slightly below the LUMO, which still indicates that
this particular excitation occurs at the HOMO witha contribution of 115.1%. The last excitation type, S0S3, occurs directly between the HOMO and the LUMO
with a contribution of 140.4%. The second interaction,
GP/C60_S_ZVD at the first excitation type S0-S1, with atransition from the HOMO to the LUMO of 140.7%,
the second excitation type with a transition between
the HOMO and slightly below the LUMO, which is still

Page 6 of 15

the HOMO with a contribution of 140.6%, and the third
excitation type with a transition between the HOMO
and two orbitals below the LUMO, which is one orbital
below the HOMO with a contribution of 139.3%. Similar transitions are recorded for GP/C60_Se_ZVD and GP/
C60_O_S_Se_ZVD. The percentage contribution ranges
from 96.1% for GP/C60_O_S_Se_ZVD S0-S3 to 164.9% for
GP/C60_O_S_Se_ZVD S0-S1. The oscillator strength (f ) isa dimensionless quantity that ranges from 0 to 1 and provides information on the probability of the transition ofelectrons. From the table, GP/C60_O_S_Se_ZVD records
the highest transition of electrons since it possesses thehighest oscillator strength of approximately 1.07 × 10− 2 inits second excitation state. The oscillation strength of GP/
C60_Se_ZVD was 0.0, which indicates that no electrons
were transferred in the third excitation type. However,
the oscillator strength (f ) is related to the dipole moment(µ) by the equation below:f ∝ µ2.
This means that as the oscillator strength increases,
the dipole moment also increases, indicating a greater
separation of charge and thus increased polarity. In thecontext of this study, the increased oscillator strengthand corresponding dipole moment enhance the electron transfer process. A larger dipole moment facilitates the transfer of electrons between molecules as it
creates a greater electric field gradient. This in turn,increases the probability of electron transfer, which is
crucial for understanding the UV-Vis absorption properties of the system. As the oscillator strength increases,
the dipole moment increases, and the polarity of thesystem increases. It was observed that GP/C60_O_S_
Se_ZVD and GP/C60_S_ZVD are more polar than GP/
C60_O_ZVD and GP/C60_Se_ZVD, suggesting to be moreconjugated.
Electronic property investigation
Chemical reactivity descriptors

The difference between the highest occupied molecularorbital (HOMO) and the lowest unoccupied molecularorbital (LUMO), known as the energy gap, is a crucial
indicator for understanding the chemical complex reactivity, electronic structure, and stability of the complex[54]. The chemical and physical properties of a complex are significantly influenced by its molecular orbital,
which is a function that characterizes the frontier molecular orbital (FMO) theory, as reported in previous studies. In this study, the energy gap is shown in Table 2
and illustrated in Fig. 3. The complex shows a variationin the surfaces and interacting complex, where the bear
surfaces possesses a lower energy gap compared to thecomplex with the medication. As shown in the table,
GP/C60_O_S_Se_ZVD had an energy gap of 1.276 eV
before interaction and 1.303 eV after interaction. The

Akor et al. BMC Chemistry(2024) 18:156

Page 7 of 15

Table 2 HOMO-LUMO results and quantum parameters such as ionization potential (IP), electron affinity (EA) chemical hardness (η),
chemical softness (σ), chemical potential (µ), electrophilicity index (ω), and Fermi energy level (EFL)
Complex
GP/C60_O
GP/C60_O_ZVD
GP/C60_O_S_Se
GP/C60_O_S_Se_ZVD
GP/C60_S
GP/C60_S_ZVD
GP/C60_Se
GP/C60_Se_ZVD

HOMO
eV-5.174-5.367-5.382-5.301-5.278-4.010-5.277-5.305LUMO
eV-3.475-3.589-4.106-3.998-3.383-3.341-3.318-3.221

Energy
gap
1.699
1.778
1.276
1.303
1.895
0.668
1.959
2.083

IP
(eV)
5.174
5.368
5.382
5.301
5.278
4.010
5.277
5.305

EA
(eV)
3.475
3.589
4.106
3.998
3.383
3.341
3.318
3.221

σ
(eV)
0.588
0.562
0.783
0.767
0.527
1.495
0.510
0.479

η
(eV)
0.849
0.889
0.638
0.651
0.947
0.334
0.979
1.041

µ
(eV)
-4.324-4.478-4.744-4.649-4.330-3.675-4.298-4.263ω(eV)
11.006
11.27817.636
16.5889.895420.2099.42628.7235EFL(eV)
4.32484.47874.74434.64984.33093.67584.29804.2633Fig. 3 Visual representation of the HOMO-LUMO isosurfaces of GP@C60_O_ZVD, GP@C60_O_S_Se_ZVD, GP@C60_S_ZVD, and GP@C60_Se_ZVD depicted in (a), (b), (c) and (d), respectively

GP/C60_O_ZVD complex had an energy gap of 1.699 eV
before interaction and 1.778 eV after interaction, and GP/
C60_Se_ZVD exhibited an energy gap of 1.959 eV before
interaction and 2.083 eV after interaction. The energies of
the GP/C60_O_S_Se_ZVD, GP/C60_O_ZVD, and GP/
C60_Se_ZVD complexes increase in the same way after
the interaction. However, for the complex GP/C60_S_
ZVD, which has an energy gap of 1.895 eV before and0.668 eV after interaction, a different trend is observed,
which also gives it a greater chance of delivering the drug
effectively than the other complexes. Chemical hardness and softness play a crucial role in confirming theresults, which explains that the ability of a chemical substance to transfer electron charge within its immediate

molecule depends on its chemical hardness and softness[55, 56]. Chemical hardness also influences the stability
and reactivity of a complex, depending on the hardnessof the complex [56]. As shown in the table, GP/C60_O_
ZVD exhibited a high chemical hardness of 0.889 eV, andGP/C60_S_ZVD had the lowest chemical hardness of
0.334 eV. To buttress the finding, the complex GP/C60_S_
ZVD is observed to have a very high chemical softness of
1.495 eV, suggesting the relative instability and reactivityof the complex. Upon interaction/complexing with thedrug separately, a decrease in softness is observed, following this trend for the complexes. GP/C60_O_S_Se_
ZVD < GP/C60_O_ZVD < GP/C60_Se_ZVD, except for
GP/C60_S_ZVD, whose values increased when it wasAkor et al. BMC Chemistry(2024) 18:156

doped from 0.527 eV to 1.495 eV. Conversely, in termsof chemical hardness, an increase is noted after doping:
the complex hardness increased except for that of GP/
C60_S_ZVD, whose values decreased from 0.947 eV to0.334 eV. This indicates an enhanced instability and reactivity of the complex after interaction with the ZVD, asevident in the values presented in the table. Furthermore,
the ionization potential values determine the stability and reactivity, where the value of the electron affinity provides insight into the types of bonds and electrontransfer, and the ionization potential signifies the interaction and stability [57]. In this study, the value of the IP
during before interaction with the ZVD molecule shows
an increasing trend of GP/C60_O < GP@C60_Se < GP@
C60_S < GP/C60_O_S_Se. Notably, the value before
interaction is less than the the complexes value, with the
exception of GP/C60_S_ZVD, where the surface is higher
than the complex by 5.278 eV, while GP/C60_O has theleast IP before interaction by 5.174 eV. Upon complexing,
the trend in its ascending order of GP/C60_S_ZVD < GP/
C60_O_S_Se_ZVD < GP/C60_Se_ZVD < GP/C60_O_
ZVD provides insight into the potency of the complex as a promising candidate for drug delivery, as GP/
C60_S_ZVD possesses the least IP value, making it very
reactive and easily releasing electrons for possible reactions in the environment. The electronegativity of GP/
C60_S_ZVD, with a value of 20.209 eV, further explains
why the complex possesses the properties needed for
effective drug delivery [58]. It can be deduced from theresults that there is a strong correlation between the calculated parameters and the delivery of zidovudine to the
GP/C60_Se surface because of the greater energy gap
upon interaction with the drug.
Second-order perturbation energy analysis

Natural bond orbital (NBO) analysis provides a localized and chemically intuitive description of the molecular electronic structure, explaining intermolecular chargetransfer [59]. Table S3 contains information on the transitions, donor and acceptor atoms, stabilization energy
values E(2), energy differences (E(j)-E(i)), and NBO overlap values (F(i, j)) for various transitions in different
compounds (GP@C60, GP@C60_O, GP@C60_S, GP@
C60_Se, GP@C60_O_ZVD, GP@C60_S_ZVD, GP@C60_
Se_ZVD, GP@C60_O_S_Se_ZVD). This study explains
the interaction between the compound and the doped
compound as well as the interaction with ZVD. The transitions involving different orbital interactions, such as
π→π*, π*→π*, LP→d*, describe the complicated natureof chemical bonding [60]. Table S3 shows the stabilization energy level obtained during the transition, whereenergy differences (E(j)-E(i)) explained energy changes
associated with specific electronic rearrangements andNBO overlap values (F(i, j)) quantify the extent of orbital

Page 8 of 15

overlap, providing a crucial parameter for understanding the strength of chemical bonds in these compounds[61]. According to the study, the greater the value of thedonor-acceptor interaction of the stabilization energy
E(2), the more stable the system. The GP@C60 compound
demonstrates π→π* transitions involving various donor
and acceptor atoms, revealing the involvement of specific carbon atoms in these bonding interactions withstabilization energies of 10.08 kcal/mol, 9.97 kcal/mol,and 15.02 kcal/mol. Additionally, the stabilization energies E(2) of the interactions GP@C60_O, GP@C60_S, andGP@C60_Se were 98.21, 75.67, and 65.20, 80.64, 55.35,
and 46.19, respectively, and the stabilization energies of
the compound GP@C60_O were 98.21, 75.67, and 65.20,
respectively. Moreover, the stabilization energies of thecompound GP@C60_S were 80.64, 55.35, and 46.19,
while those of GP@C60_Se was 84.50, 93.21, and 76.22,
respectively. However, the complexes that interact withZVD are GP@C60_O_ZVD, GP@C60_S_ZVD, GP@
C60_Se_ZVD, and GP@C60_O_S_Se_ZVD, which are
43.74, 21.83, 60.01 and 96.44 kcal/mol; 75.87, 47.76 and66.98, 96.17, 71.40 kcal/mol; and 80.38, 76.42, 65.42 kcal/
mol, respectively. Upon interacting GP@C60 with oxygen, sulfur, and selenium, there was a notable increase in
the stabilization energy of the system, indicating intenseintermolecular charge transfer. Furthermore, it is worth
noting that the system again interacted with ZDV, andthere was both an increase and a decrease in the stabilization energy. Notably, the overall prominent transition
that took place in the system was π → π* before the interaction with ZVD, and in the other way, the prominenttransition changed from π→ π* to π* → π*. Hence, themajor transitions occurred with π* → π*, contributing to
the stability characteristic observed in the systems.
Density of states (DOS) analysis

The density of states (DOS) is employed to simulate
and predict the electronic structure of materials accurately and determine the distribution of electrons among
the individual contributing molecules [62]. Similarly,
in quantum mechanics, the DOS represents the number of electronic states per unit energy interval at eachenergy level [63]. Different density of states parameters
is employed in the determination of the electronic properties of the studied compound, which are the total density of states (TDOS), overlap partial density of states(OPDOS), and partial density of states (PDOS). The studied compound is composed of carbon (C), hydrogen (H),sulfur (S), oxygen (O), nitrogen (N), and selenium (Se)atoms, with each atom represented by a colour notation. From the results of this study, as shown in Figure
S1, the carbon atom shows the highest orbital contribution in all the systems. Moreover, the Fermi energy levels of -6.78 eV, -6.78 eV, -6.89 eV, and − 6.89 eV for GP/

Akor et al. BMC Chemistry(2024) 18:156

Page 9 of 15

C60_O_ZVD, GP/C60_S_ZVD, GP/C60_Se_ZVD, andGP/C60_O_Se_ZVD, respectively, are expressed withdotted lines. This shows non-dispersible changes in theenergy fermi level of the compounds. The DOS is vital for
designing new materials with specific electronic properties or understanding the behaviour of existing materials
under different conditions because of the utilization of
the studied nanocomposites in the delivery of drugs.
Visual studies
Analysis of the quantum theory of atoms-in-molecules(QTAIM)QTAIM analysis was employed to thoroughly investigate the nature of the interactions between atoms within
a molecule. This approach was applied to understandhow interactive and stable our studied delivery material
would be following interaction with the understudy ZVD[64, 65]. QTAIM studies have gained wide acceptance indrug delivery studies because they encompass importantparameters that reveal different interactive behaviours
via bond critical points [66]. The AIM molecular graphsof GP/C60_O_ZVD, GP/C60_S_ZVD, GP/C60_Se_ZVD,
and GP/C60_O_Se_ZVD are shown in Figure S2, while
the statuses of all the bond points and bond criticalpoints related to these complexes are indicated in boththe figure and Table 3. As presented in the table, all thecomplexes exhibited a large increase in the Laplaciancharge density, demonstrating a decrease in the charge
density between the adsorbent and the ZVD fragments.
Thus, these trends present the typical characteristics ofclosed-shell interactions, indicating noncovalent interactions [67]. The value of ∇2 ρ(r) at the intermolecularhydrogen bond critical points of the GP@C60_S_ZVD
complex was greater (0.0752 a.u. at H124-H131 bonding)than that of the other complexes, which confirmed thatthe greatest electronic change occurred in the nanoparticles despite intermolecular interactions with ZVD.
This suggests enhanced stability and potentially stronger
interactions, which are crucial for maintaining the integrity and efficacy of drug delivery systems. Conversely, thelocalization and delocalization of electrons within a molecule were investigated through the electronic localization function (ELF), where a value less than zero indicateshigh delocalization. In contrast, a value greater than zero
indicates localization regions [68]. Based on our results,
the overall complexes exhibit delocalization of electrons
at most of their critical points. However, the lowest values were observed for S93-N107 and 217a.u. for GP@

Table 3 QTAIM results for the investigated complexes showing the critical point (CP), density of all electrons ρ(r), Laplacian of thecharge density ∇2 ρ(r), kinetic energy density G(r), hamiltonian kinetic energy K(r), potential energy density V(r), energy density H(r),and electron localization function (ELF)
SYSTEMS

BONDS

GP@C60_O_S_Se_ZVD

S93-C98
Se96-C109
C15-O110
O95-N108
S93-N107
C26-C98
O96-N105
C16-C100
C24-H115
C16-H113
C24-N123
S96-H121
C123-C98
H124-H131
C24-C99
H115-O122
C18-N110
C51-H128
C23-H102
C24-N103
C25-N104
Se96-O116
C48-H119
C26-O124
C49-N120

GP@C60_O_ZVD

GP@C60_S_ZVD

GP@C60_Se_ZVD

CP
(a.u)
166
218
231
297
217
151
181
198
288
246
322
288
237
369
168
287
176
139
168
212
214
269
250
301
181

ρ(r)
(a.u)
0.00720.11670.00830.01010.00560.00910.00220.00520.00590.00650.00960.00920.00610.01500.00750.01780.00820.00640.00800.00970.00870.01480.01200.00910.0014∇2ρ(r)(a.u)
0.02300.04720.03260.04940.02220.02330.01720.01540.02190.02120.02940.03030.01700.07520.02190.07240.02760.02130.02200.03180.0291
0.05840.0407
0.03680.0094V(r)(a.u)-0.0465-0.0081-0.0048-0.0095-0.0033-0.0052-0.0018-0.0025-0.0032-0.0032-0.0062-0.0041-0.0030-0.0142-0.0044-0.0158-0.0053-0.0035-0.0049
0.0066-0.0058-0.0113-0.0066-0.0062-0.0009G(r)(a.u)
0.05880.00100.00650.01090.00440.00550.00300.00320.00430.00430.00680.005830.00360.01650.00490.01700.00610.00440.00520.00730.00650.01300.00840.00770.0016K(r)(a.u)-0.0123-0.0018-0.0017-0.0014-0.0011-0.0008-0.0012-0.0007-0.0011-0.0010-0.0006-0.0018-0.0006-0.0023-0.0006-0.0011-0.0008-0.0009-0.0003-0.0007-0.0008-0.0016-0.0018-0.0015-0.0007H(r)(a.u)
0.01230.00180.00170.00140.00110.00080.00120.00070.00110.00100.00060.00180.00060.00230.00060.00110.00080.00090.00030.00070.00080.00160.00180.00150.0007

ELF(a.u)
0.04240.02890.02240.01530.01270.04020.00120.01870.01670.02290.03240.03750.02570.02470.02730.03100.02360.01940.03030.02950.0256
0.03760.0441
0.02110.0009Akor et al. BMC Chemistry(2024) 18:156

C60_O_S_Se_ZVD; for O96-N105 and 181a.u. for GP@
C60_O_ZVD; for C18-N110 and 176a.u. for GP@C60_S_
ZVD; and for C49-N120 and 131a.u., respectively. Thisimplies that the electrons of atoms within these bonds
are easily delocalized. Despite having ELF values < 0, theGP@C60_S_ZVD complex had higher values than theother complexes. Therefore, higher ELF values observed
at most of the critical point implies strong interactions
between the drug and carrier, promoting stability andcontrolled release dynamics. Additionally, the stability of
the interactions can also be accounted for by the interaction between electrons and nuclei of the system, basedon the values of potential energy density V(r), as higher
negative values indicate significantly stronger interactions. Herein, the V(r) values were negative across all thecritical points recorded for all the complexes. This suggests attractive interactions between the drug and thecarrier, which can enhance stability by promoting complex formation.
Noncovalent interaction studies

NCI serves as a critical tool for assessing the tenacity of
intra- and intermolecular interactions, providing insight
into the bonding between drug delivery systems anddrugs, especially in the context of targeted therapies.
However, in drug delivery studies, the primary goal is toPage 10 of 15transport therapeutic compounds to their intended siteof action with precision and efficiency while minimizing off-target effects. Therefore, achieving this objective
requires the evaluation of interactions between the drug
and delivery material; hence, this study highlights thedifferent natures of interactions/bonds that exist in thestudied complexes, ranging from van der Waals interactions to hydrogen bond interactions and steric repulsion[69]. The study utilized a Multiwfn analyzer and visual
molecular dynamic visualization tool to plot and extract
the colours of the kinds of interactions present. The literature has reported that blue, green, and red spatial
fragments represent different kinds of intermolecularinteractions, where red signifies strong interactions solely
due to steric repulsion, the green zone represents weakvan der Waals forces within the studied compound, andthe blue zone represents hydrogen bonding [70–72]. As
noted from the results of the analysis for this investigation in Fig. 4, all four interactions exhibit large green
isosurfaces within their intermolecular interactions.
This reveals a weak force of interaction, highlighting theability of the delivery material to easily release the ZVD
compound. This effect was notable between the two combined nanoparticles, indicating that an electrostatic force
existed between them, which could be the result of theproperties of the atoms present and their conformational

Fig. 4 Noncovalent interaction analysis identifying the nature of intermolecular interaction

Akor et al. BMC Chemistry(2024) 18:156

Page 11 of 15

arrangements. Likewise, a large red band was observed
for the intramolecular delivery system, while a few red
signals were observed for the intramolecular delivery
system of the ZXD compound, indicating the presenceof strong and weak steric effects, respectively. Generally,
this implies that the three-dimensional arrangement of
atoms within a molecule significantly impacts its reactivity, stability, and behaviour due to the repulsive interactions between electrons and nearby atoms.
Adsorption energy/BSSE analysis

Adsorption energy is an important aspect of the interaction between adsorbates and surfaces and plays an important role in understanding and optimizing processes indifferent fields, for instance, in the fields of catalysis gas
storage and environmental remediation [73]. The adsorption energy is typically expressed in units of energy per
absorbate molecule in kJ/mol or eV, as shown in Table 4,
and the adsorption energy is also the energy change
associated with the adsorption process. The adsorptionenergy was computed using the following equation:

Eads = Ecomplex − (Eadsorbate + Esurface)where Ead is the adsorption energy, Ecomplex is the energyof the interaction (adsorbate on the surface), E adsorbate
is the energy of the isolated adsorbate and Esurface is theenergy of the clean surface. Adsorption energy analysis
can be said to be more favorable if the reaction process is
exothermic (negative adsorption) < 0, while an endothermic process (positive adsorption) ≥ 0 implies less favourable adsorption [74]. Adsorption energy is a valuable toolthat can be applied to predict the stability and efficiencyof the adsorption process. A strong adsorption energy
often corresponds to a stable configuration, resulting ina strong interaction between the adsorbate and the surface. However, weak adsorption, which in this instance isa positive adsorption energy value, may result in reversible adsorption, making surface properties important
for a specific application. According to our results, all
the complexes exhibit negative adsorption energies (GP/
C60_S_ZVD − 1.599 eV, GP/C60_Se_ZVD − 0.400 eV,
GP/C60_O_ZVD − 0.403 eV, and GP/C60_O_S_Se_ZVD− 0.390 eV), implying exothermic interactions. In otherwords, the complexity between the studied delivery

materials and ZVD results in better adsorption, which
is an important tool for drug delivery. Even at basis set
superposition error (BSSE) evaluation, the systems
remain consistent at the same adsorption phenomena,
thereby demonstrating a tenacious adsorption capacity.
Comparatively, the graphene-doped fullerene (C60) alongwith doped sulfur in the GP/C60_S (-1.599 eV) complex
is considered suitable for drug delivery, especially for
ZVD, and this more exothermic process is attributed tothe conformation of the delivery system, where sulfur
plays a significant role in surface engineering.
Drug release, pH, and dipole moment studies

The effectiveness and efficacy of how the nanomaterial will deliver the drug to the target site were determined by determining the parameters of the drug releasemechanism, whereas the dipole moment was studied todetermine the nature of the charge distribution within
the system, and a pH evaluation showed how the environmental parameters influence the nanoparticle andhow zidovudine (ZVD) can be released in the system[75–77]. This study investigated the effect of PH on zidovudine (ZVD) released from GP/C60_S, GP/C60_Se,
GP/C60_O, and GP/C60_O_S_Se, which is a theoreticalaspect of drug delivery in living systems. The impact ofpH on drug release is a critical factor in drug development because it can significantly affect the solubility, stability, and release kinetics of pharmaceutical compounds.
The study aimed to elucidate pH-dependent behaviours
and their implications for drug release mechanisms from
GP/C60-based systems. The pH influences drug releasethrough its effect on the solubility and ionization state ofboth the drug and the carrier materials. At different pH
levels, protonation or deprotonation of functional groups
on the carrier surface can alter electrostatic interactions
with the drug molecules, affecting their release kinetics[78]. Therefore, drug release values reported in atomic
units (a.u.) provide insights into the release potential ofzidovudine (ZVD) from different formulations. Interestingly, the drug release values varied across the various systems, as presented in Table 5, suggesting that thenature of the adsorption energy and the specific interactions between the drug and its carrier play a role in modulating drug release. Notably, GP/C60_S_ZVD exhibitedthe highest drug release value (-0.578 a.u.), indicating a

Table 4 The adsorption energy result, including E_complex (complex energy), E_adsorbate (adsorbate energy), E_adsorbent(adsorbent energy), given in Hartree units and Basis set superposition error (BSSE)
Complexes

Ecomplex (Hartree)

Eadsorbate (Hartree)

Adsorption energy (eV)BSSE

GP/C60_S_ZVD
GP/C60_Se_ZVD
GP/C60_O_ZVD
GP/C60_O_S_Se_ZVD-4530.820-6532.831-4206.629-6929.910-3566.164-5569.374-3243.170-5966.463-1.599-0.400-0.403-0.3900.01000
0.014420.00875
0.00859

Ads + BSSE
(eV)
-1.589-0.386-0.394-0.381

Akor et al. BMC Chemistry(2024) 18:156

Page 12 of 15

Table 5 Results from the analysis of drug release (a.u.), solvationenergy (eV), and dipole moment (D)Systems

GP/C60_S_ZVD
GP/C60_Se_ZVD
GP/C60_O_ZVD
GP/C60_O_S_Se_ZVD

Drugrelease(a.u)-0.578-0.487-0.515-0.509

Solvationenergy(eV)-0.825-0.662-0.713-0.681

Dipolemoment(D)
6.480074
4.203098
3.804473
3.019110

tendency towards a less constrained release mechanism
compared to GP/C60_Se_ZVD (-0.487 a.u.), GP/C60_O_
ZVD (-0.515 a.u.), and GP/C60_O_S_Se_ZVD (-0.509
a.u.), suggesting potentially easier desorption under similar conditions. Furthermore, an examination of the dipole
moment was conducted for each system to determine thenature of the charge distribution within the investigatedsystems and how drug molecules interact [79]. The dipole
moment values were determined to be 6.480D, 4.203D,
3.804D, and 3.012D for GP/C60_S_ZVD, GP/C60_Se_
ZVD, GP/C60_O_ZVD, and GP/C60_O_S_Se_ZVD,
respectively. This suggests that the GP/C60_S_ZVD(6.480D) complex is more unlikely to separate due to theelectrostatic forces between the adsorbate and adsorbent,
as indicated by noncovalent interaction studies. Whileother systems with a dipole moment of less than 5D
undergo quick desorption.
Solvation energy studies

In the development of a suitable drug delivery system,
solvation energy explains the dynamics of solute-solvent
interactions, which can be implemented in the field of
drug delivery to assess the interaction between a drug
and delivery material [80, 81]. The solvation energy
denotes the energy variation that occurs when a drug
molecule interacts with the molecule of delivery material. This energy change signifies the strength and natureof the bond formed between them. The solvation process typically involves the breaking of existing nanoparticle-nanoparticle and drug‒drug interactions, followedby the formation of new nanoparticle-drug bonds [82].
This rearrangement of molecules results in an energychange within the system. The solvation energy, therefore, quantifies this energy change, providing a measureof the affinity between the nanoparticle and drug [83,84]. A solvation ≥ 0 energy indicates an endothermic process, meaning that energy is adsorbed as the nanoparticle
interacts with the drug. This suggests a weaker interaction between the nanoparticles and drug molecules.
Conversely, solvation < 0 energy denotes an exothermic process, where energy is released during solvation,
implying a stronger attraction between the nanoparticles
and drug molecules. The observed solvation energies
in the systems are predominantly small and negative,

indicating favourable interactions with the Zidovudine(ZVD) drug (Table 5). Notably, GP/C60_S_ZVD and GP/
C60_O_ZVD exhibit the most negative solvation energies, measured at -0.825 eV and − 0.713 eV, respectively.
This finding underscores the enhanced solvation interactions with ZVD brought about by incorporating sulfur (S)and oxygen (O) atoms in co-surface engineering, suggesting that these systems are highly useful for ZVD delivery.
Conversely, GP/C60_Se_ZVD and GP/C60_O_S_Se_
ZVD display marginally less negative solvation energies, recorded at -0.662 eV and − 0.681 eV, respectively.
Although still indicative of favourable interactions, thesevalues suggest that the initial GP/C60_Se_ZVD system
and its derivative with added S and O atoms may exhibit
slightly weaker solvation interactions with ZVD thansystems lacking selenium (Se) atoms. This phenomenon
might arise from the broader electronegativity of selenium, contributing to the relatively less attractive characteristics of the investigated delivery systems. In general,
the incorporation of specific atoms, such as S, O, and Se,
in the co-surface engineering of graphene-based systems
has visible effects on solvation energies, influencing theattractiveness and effectiveness of these systems for ZVD
delivery. Understanding these dynamics aids in the rational design and optimization of custom-made drug delivery platforms for specific therapeutic agents.

Conclusions
Encapsulating antiretroviral drugs within nanoparticles is an excellent innovation for precise drug delivery.
Therefore, in this study, we re-engineered nanoparticles
by combining two surfaces, namely, graphene and fullerene C60, and modified with sulfur (S), selenium (Se), andoxygen (O) for the delivery of zidovudine (ZVD) using
density functional theory (DFT) simulations, whichwere calculated with the B3LYP functional and D3(BJ)/
Def2svp basis sets. Moreover, the modification of theaforementioned elements could enhance the attractiveness of the studied delivery material, thereby facilitating
the delivery of ZVD. In our research, a structural study
was performed to determine the structural changes that
occurs on customized delivery materials and their interactions with ZVD. Most of the selected bond labels displayed decreased bond lengths after interaction with
ZVD, indicating stable interactions. However, the afterbond length of GP@C60_S_ZVD was shorter than thatof the other materials, implying better stability. Further
evidence of a stable nature was obtained in second-order
perturbation energy analysis where the π* → π* transition is predominant among the systems. In addition, theGP/C60_S_ZVD (0.668 eV) and GP/C60_O_S_Se_ZVD
systems exhibited favourable interactions following the
HOMO-LUMO energy gap. The energy gap showeddecrease in the order GP/C60_Se_ZVD (2.083 eV) > GP/Akor et al. BMC Chemistry(2024) 18:156

C60_O_ZVD (1.778 eV) > GP/C60_O_S_Se_ZVD (1.303
eV) > GP/C60_S_ZVD (0.668 eV). Visual studies, especially quantum theory of atoms-in-molecules (QTAIM)
and noncovalent interactions (NCIs), have revealed theintramolecular and intermolecular interactions of thecomplexes. The findings show that all the studied systems involve noncovalent interactions rather than covalent interactions, providing good characteristics for ZVD
delivery. Further investigations in NCI studies revealed
intermolecular steric repulsion via intramolecular andvan der Waals interactions across all the tested systems. The sensitivity of the delivery materials to ZVD
was revealed through the Fermi energy density of state
results. The Fermi energy levels of GP/C60_O_ZVD,
GP/C60_S_ZVD, GP/C60_Se_ZVD, and GP/C60_O_
Se_ZVD are − 6.78 eV, -6.78 eV, -6.89 eV, and − 6.89 eV,
respectively. This shows a similarity in sensitivity capacity; hence, despite the variation in doped atoms, they possessed a similar nature in terms of sensitivity. Their levelof interaction was further studied via adsorption energy,
whereby GP/C60_S_ZVD, GP/C60_O_ZVD, GP/C60_
Se_ZVD, and GP/C60_O_S_Se_ZVD had energies of-1.59949 eV, -0.40265 eV, -0.40007 eV, and − 0.39032 eV,
respectively. The mechanism of drug release was investigated through pH and dipole moment, where GP/C60_S_
ZVD was indicated to have the highest dipole moment(6.480074 D), suggesting quick release. However, thedipole moments of GP/C60_Se_ZVD, GP/C60_O_ZVD,
and GP/C60_O_S_Se_ZVD are 4.203098 D, 3.804473 D,
and 3.019110 D, respectively, which provide a significant
model for the subsequent delivery of the zidovudine drugin cases of HIV/AIDs infection.

Supplementary Information

The online version contains supplementary material available at https://doi.
org/10.1186/s13065-024-01259-3.
Supplementary Material 1
Author contributions
I.B: Project conceptualization, design, methodology. B.O.E. and S.O.I:
Investigation, supervision, and editing: F.O.A., F.A.N., and E.G.: Visualization,
analysis, writing manuscript first draft: A.U.J. and M.N.A: Proofreading, editing,
and writing. A.O.G and C.B.U: Editing, writing, and revision.
Funding information
This research was carried out without funding from the government or any
other third party.
Data availability
No datasets were generated or analysed during the current study.

Declarations
Competing interests
The authors declare no competing interests.

Page 13 of 15

Ethics approval and consent to participate
Not applicable.
Consent for publication
Not applicable.
Competing interests
All authors declare zero financial or interpersonal conflict of interest that could
have influenced the research work or results reported in this research paper.
Received: 3 April 2024 / Accepted: 2 August 2024

References
1. Abbott KC, Hypolite I, Welch PG, Agodoa LY. Human immunodeficiency virus/
acquired immunodeficiency syndrome-associated nephropathy at end-stage
renal disease in the United States: patient characteristics and survival in the
pre highly active antiretroviral therapy era. J Nephrol. 2001;14(5):377–83.
2. Kushnir VA, Lewis W. Human immunodeficiency virus/acquired immunodeficiency syndrome and infertility: emerging problems in the era of highly
active antiretrovirals. Fertil Steril. 2011;96(3):546–53.
3. Weng HB, Chen HX, Wang MW. Innovation in neglected tropical disease drug
discovery and development. Infect Dis Poverty. 2018;7(03):1–9.
4. Ankrah EM. AIDS and the social side of health. Soc Sci Med.
1991;32(9):967–80.
5. Petryna A, Biehl J. (2013). When people come first: critical studies in global
health.
6. Richman DD, Margolis DM, Delaney M, Greene WC, Hazuda D, Pomerantz RJ. The challenge of finding a cure for HIV infection. Science.
2009;323(5919):1304–7.
7. World Health Organization. The world health report 2003: shaping the future.
World Health Organization; 2003.
8. Salehi B, Kumar NVA, Şener B, Sharifi-Rad M, Kılıç M, Mahady GB, Sharifi-Rad J.
Medicinal plants used to treat human immunodeficiency virus. Int J Mol Sci.
2018;19(5):1459.
9. D’Aquila RT, Hughes MD, Johnson VA, Fischl MA, Sommadossi JP, Liou SH,
Hirsch MS. Nevirapine, zidovudine, and didanosine compared with zidovudine and didanosine in patients with HIV-1 infection: a randomized, doubleblind, placebo-controlled trial. Ann Intern Med. 1996;124(12):1019–30.
10. Raulin J. Human immunodeficiency virus and host cell lipids. Interesting
pathways in research for a new HIV therapy. Prog Lipid Res. 2002;41(1):27–65.
11. Sharma B. (2011). Anti-HIV-1 drug toxicity and management strategies.
Neurobehavioral HIV Med, 27–40.
12. Lu DY, Wu HY, Yarla NS, Xu B, Ding J, Lu TR. HAART in HIV/AIDS treatments:
future trends. Infect Disorders-Drug Targets (Formerly Curr Drug TargetsInfectious Disorders). 2018;18(1):15–22.
13. Bertozzi S, Padian NS, Wegbreit J, DeMaria LM, Feldman B, Gayle H, Isbell MT.
HIV/AIDS prevention and treatment. Disease Control Priorities Developing
Ctries. 2006;2:331–70.
14. Fang C, Yoon S, Tindberg N, Järveläinen HA, Lindros KO, Ingelman-Sundberg
M. (2004). Hepatic expression of multiple acute phase proteins and downregulation of nuclear receptors after acute endotoxin exposure.
15. Kharwade R, Mahajan NM. Role of nanocarriers for the effective delivery ofanti-HIV drugs. Photophysics and Nanophysics in therapeutics. Elsevier; 2022.
pp. 291–310.
16. Giacalone G, Hillaireau H, Fattal E. Improving bioavailability and biodistribution of anti-HIV chemotherapy. Eur J Pharm Sci. 2015;75:40–53.
17. Boyd DB. How computational chemistry became important in the pharmaceutical industry. Rev Comput Chem. 2007;23:401.
18. Thakur S, R., Agrawal R. Application of nanotechnology in pharmaceuticalformulation design and development. Curr Drug Therapy. 2015;10(1):20–34.
19. Suttee A, Singh G, Yadav N, Barnwal P, Singla R, Prabhu N, K. S., Mishra V. A
review on status of nanotechnology in pharmaceutical sciences. Int J Drug
Deliv Technol. 2019;9:98–103.
20. Petlin DG, Amarah AA, Tverdokhlebov SI, Anissimov YG. A fiber distribution model for predicting drug release rates. J Controlled Release.
2017;258:218–25.
21. Ilinskaya AN, Shah A, Enciso AE, Chan KC, Kaczmarczyk JA, Blonder J,
Dobrovolskaia MA. Nanoparticle physicochemical properties determine theAkor et al. BMC Chemistry

22.
23.
24.
25.
26.

27.
28.
29.

30.
31.
32.

33.

34.
35.
36.
37.
38.
39.

40.

41.
42.
43.

(2024) 18:156

activation of intracellular complement. Nanomed Nanotechnol Biol Med.
2019;17:266–75.
Amin MK, Boateng JS. Surface modification of mobile composition of matter(MCM)-41 type silica nanoparticles for potential oral mucosa vaccine delivery.
J Pharm Sci. 2020;109(7):2271–83.
Pradhan D, Biswasroy P, Goyal A, Ghosh G, Rath G. Recent advancement in
nanotechnology-based drug delivery system against viral infections. AAPS
PharmSciTech. 2021;22:1–19.
Dahmane EM, Rhazi M, Taourirte M. Chitosan nanoparticles as a newdelivery system for the anti-HIV drug zidovudine. Bull Korean Chem Soc.
2013;34(5):1333–8.
Joshy KS, Susan MA, Snigdha S, Nandakumar K, Laly AP, Sabu T. Encapsulationof zidovudine in PF-68 coated alginate conjugate nanoparticles for anti-HIV
drug delivery. Int J Biol Macromol. 2018;107:929–37.
Gupta S, Kesarla R, Omri A. Approaches for CNS delivery of drugs–nose-tobrain targeting of antiretroviral agents as a potential attempt for complete
elimination of major reservoir site of HIV to aid AIDS treatment. Expert Opin
Drug Deliv. 2019;16(3):287–300.
Choi CH, Chung MW, Jun YJ, Woo SI. Doping of chalcogens (sulfur and/or
selenium) in nitrogen-doped graphene–CNT self-assembly for enhanced
oxygen reduction activity in acid media. RSC Adv. 2013;3(30):12417–22.
Xia J, Li F, Ji S, Xu H. Selenium-functionalized graphene oxide that canmodulate the balance of reactive oxygen species. ACS Appl Mater Interfaces.
2017;9(25):21413–21.
Niranjan R, Zafar S, Lochab B, Priyadarshini R. Synthesis and characterizationof sulfur and sulfur-selenium nanoparticles loaded on reduced graphene
oxide and their antibacterial activity against gram-positive pathogens. Nanomaterials. 2022;12(2):191.
Clancy AJ, Bayazit MK, Hodge SA, Skipper NT, Howard CA, Shaffer MS.
Charged carbon nanomaterials: redox chemistries of fullerenes, carbon
nanotubes, and graphenes. Chem Rev. 2018;118(16):7363–408.
Visic B, Panchakarla LS, Tenne R. Inorganic nanotubes and fullerene-like
nanoparticles at the crossroads between solid-state chemistry and nanotechnology. J Am Chem Soc. 2017;139(37):12865–78.
Xu Z, He M, Zhou Y, Nie S, Wang Y, Huo Y, Chen X. Spider web-like carbonized bacterial cellulose/MoSe 2 nanocomposite with enhanced microwave attenuation performance and tunable absorption bands. Nano Res.
2021;14:738–46.
Guan M, Ge J, Wu J, Zhang G, Chen D, Zhang W, Shu C. Fullerene/photosensitizer nanovesicles as highly efficient and clearable photo theranostics
with enhanced tumor accumulation for cancer therapy. Biomaterials.
2016;103:75–85.
Lin MS, Chen RT, Yu NY, Sun LC, Liu Y, Cui CH, Zheng LS. Fullerene-based
amino acid ester chlorides are self-assembled as spherical nanovesicles for
drug-delayed release. Colloids Surf B. 2017;159:613–9.
Zaghmarzi FA, Zahedi M, Mola A, Abedini S, Arshadi S, Ahmadzadeh S, Yoosefian M. Fullerene-C60 and crown ether doped on C60 sensors for high sensitive detection of alkali and alkaline earth cations. Physica E. 2017;87:51–8.
Rahmanifar E, Yoosefian M, Karimi-Maleh H. Electronic properties and reactivity trend for defect functionalization of single-walled carbon nanotube with
B, Al, Ga atoms. Synth Met. 2016;221:242–6.
Ho PC, Wang JZ, Meloni F, Vargas-Baca I. Chalcogen bonding in materials
chemistry. Coord Chem Rev. 2020;422:213464.
Singh J, Jamdagni P, Jakhar M, Kumar A. Stability, electronic and mechanicalproperties of chalcogen (Se and Te) monolayers. Phys Chem Chem Phys.
2020;22(10):5749–55.
Grimme S, Antony J, Ehrlich S, Krieg H. A consistent and accurate ab initio
parametrization of density functional dispersion correction (DFT-D) for
the 94 elements H-Pu. J Chem Phys. 2010;132(15):154104. https://doi.
org/10.1063/1.3382344.
Weigend F, Ahlrichs R. Balanced basis sets of split valence, triple zeta
valence and quadruple zeta valence quality for H to rn: design and assessment of accuracy. Phys Chem Chem Phys. 2005;7(18):3287–97. https://doi.
org/10.1039/B508541A.
Frisch ME, Trucks GW, Schlegel HB, Scuseria GE, Robb MA, Cheeseman JR, Fox
DJ. (2016). Gaussian 16, revision C. 01.
Dennington R, Keith. TA, Millam. JM. GaussView 6.0. 16. Semichem Inc.: Shawnee Mission, KS, USA. HyperChem, T. (2001). HyperChem 8.07, HyperChem
Professional Program. Gainesville, Hypercube. 2016.
Chemcraft V. 1.8; Graphical Software for Visualization of Quantum Chemistry
Computations.

Page 14 of 15

44. Lu L, Li C, Rice JA. (2011, January). A software-defined multifunctional radar
sensor for linear and reciprocal displacement measurement. In 2011 IEEE Topical Conference on Wireless Sensors and Sensor Networks (pp. 17–20). IEEE.
45. Allouche AR. Gabedit—A graphical user interface for computational chemistry software. J Comput Chem. 2011;32(1):174–82.
46. Zhou J, Lin Z, Ju Y, Rahim MA, Richardson JJ, Caruso F. Polyphenol-mediatedassembly for particle engineering. Acc Chem Res. 2020;53(7):1269–78.
47. Bader RF. Bond paths are not chemical bonds. J Phys Chem A.
2009;113(38):10391–6.
48. Coates J. (2000). Interpretation of infrared spectra, a practical approach.
49. Fumoto E, Sato S, Takanohashi T. Determination of carbonyl functional groups
in heavy oil using infrared spectroscopy. Energy Fuels. 2020;34(5):5231–5.
50. Phan V, Quirico T, Beck E, Le Brech Y, Jovanovic L, Le Guillou C, Raya J. Infrared
spectroscopy quantification of functional carbon groups in kerogens andcoals: a calibration procedure. Spectrochim Acta Part A Mol Biomol Spectrosc. 2021;259:119853.
51. Williams ER, Steiner RL, Newell DB, Olsen PT. Accurate measurement of the
Planck constant. Phys Rev Lett. 1998;81(12):2404.
52. Sugiyama Y, Kashimura T, Kashimoto K, Akamatsu D, Hong FL. Precision dualcomb spectroscopy using wavelength-converted frequency combs with low
repetition rates. Sci Rep. 2023;13(1):2549.
53. Kryjevskaia M, Stetzer MR, Heron PR. Student understanding of wave behavior at a boundary: the relationships among wavelength, propagation speed,and frequency. Am J Phys. 2012;80(4):339–47.
54. Djurovich PI, Mayo EI, Forrest SR, Thompson ME. Measurement of the lowest
unoccupied molecular orbital energies of molecular organic semiconductors.
Org Electron. 2009;10(3):515–20.
55. Zhang G, Musgrave CB. Comparison of DFT methods for molecular orbital
eigenvalue calculations. J Phys Chem A. 2007;111(8):1554–61.
56. Zhan CG, Nichols JA, Dixon DA. Ionization potential, electron affinity,
electronegativity, hardness, and electron excitation energy: molecularproperties from density functional theory orbital energies. J Phys Chem A.
2003;107(20):4184–95.
57. Fang J, Li J. Quantum chemistry study on the relationship between molecular structure and corrosion inhibition efficiency of amides. J Mol Struct(Thoechem). 2002;593(1–3):179–85.
58. Huang Y, Rong C, Zhang R, Liu S. Evaluating frontier orbital energy and
HOMO/LUMO gap with descriptors from density functional reactivity theory.
J Mol Modelling. 2017;23:1–12.
59. Weinhold F. Discovering chemistry with natural bond orbitals. Wiley; 2012.
60. Weinhold F. Natural bond orbital analysis: a critical overview of relationships
to alternative bonding perspectives. J Comput Chem. 2012;33(30):2363–79.
61. Reed AE, Weinhold F. Natural localized molecular orbitals. J Chem Phys.
1985;83(4):1736–40.
62. Fung V, Hu G, Ganesh P, Sumpter BG. Machine-learned features from thedensity of states for accurate adsorption energy prediction. Nat Commun.
2021;12(1):88.
63. Barone V, Hod O, Peralta JE, Scuseria GE. Accurate prediction of the electronic
properties of low-dimensional graphene derivatives using a screened hybrid
density functional. Acc Chem Res. 2011;44(4):269–79.
64. Mahmoudi F, Shahraki M. Computational study of inclusion complexes ofV-type nerve agents (VE, VG, VM, VR and VX) with β-cyclodextrin. J Biomol
Struct Dynamics. 2024;42(5):2681–97.
65. Makiabadi B, Zakarianezhad M, Behjatmanesh-Ardakani R, Mousavi SH.
Investigating the performance of BN nanotubes as drug delivery systems for
Azacitidine and decitabine anti-cancer drugs: a theoretical study. Comput
Theor Chem. 2024;1231:114429.
66. Barathan U, Selvaraj S, Kadaikunnan S, Abbas G, Sambantham M. Molecularlevel interaction, electrons excitation properties, solvent effect using IEFPCM
investigation, topological surface, and docking analysis of 4-pyrrolidin-2-ylpyridine. Z fÃ¼r Phys Chem. 2024;238(4):707–28.
67. Niknam P, Jamehbozorgi S, Rezvani M, Izadkhah V. Understanding delivery
and adsorption of Flutamide drug with ZnONS based on: Dispersion-corrected DFT calculations and MD simulations. Physica E. 2022;135:114937.
68. Aghahosseini A, Edjlali L, Jamehbozorgi S, Rezvani M, Ghasemi E. Theoreticalinvestigations of functionalization of graphene and ZnO monolayers withmercaptopurine at aqueous media: A dispersion-corrected DFT calculations
and molecular dynamic simulations. J Mol Liq. 2023;369:120865.
69. Shtepliuk I, Yakimova R. Interaction of epitaxial graphene with heavy metals:
towards novel sensing platform. Nanotechnology. 2019;30(29):294002.

Akor et al. BMC Chemistry(2024) 18:156

70. Liu Z, Lu T, Chen Q. Intermolecular interaction characteristics of the allcarboatomic ring, cyclo [18] carbon: Focusing on molecular adsorption andstacking. Carbon. 2021;171:514–23.
71. Mahadevi AS, Sastry GN. Cooperativity in noncovalent interactions. Chem
Rev. 2016;116(5):2775–825.
72. Verevkin SP, Kondratev SO, Zaitsau DH, Zherikova KV, Ludwig R. Quantification and understanding of noncovalent interactions in molecular and ionicsystems: Dispersion interactions and hydrogen bonding analysed by thermodynamic methods. J Mol Liq. 2021;343:117547.
73. Johnson ER, Keinan S, Mori-Sánchez P, Contreras-García J, Cohen AJ, Yang W.
Revealing noncovalent interactions. J Am Chem Soc. 2010;132(18):6498–506.
74. Gao W, Chen Y, Li B, Liu SP, Liu X, Jiang Q. Determining the adsorptionenergies of small molecules with the intrinsic properties of adsorbates andsubstrates. Nat Commun. 2020;11(1):1196.
75. Tu X, Xu H, Li C, Liu X, Fan G, Sun W. Adsorption performance of boron nitride
nanomaterials as effective drug delivery carriers for anticancer drugs basedon density functional theory. Comput Theor Chem. 2021;1203:113360.
76. Ulbrich K, Hola K, Subr V, Bakandritsos A, Tucek J, Zboril R. Targeted
drug delivery with polymers and magnetic nanoparticles: covalent andnoncovalent approaches, release control, and clinical studies. Chem Rev.
2016;116(9):5338–431.
77. Mohammadzaheri M, Jamehbozorgi S, Ganji MD, Rezvani M, Javanshir
Z. Toward functionalization of ZnO nanotubes and monolayers with
5-aminolevulinic acid drugs as possible nanocarriers for drug delivery:a DFT based molecular dynamic simulation. Phys Chem Chem Phys.
2023;25(32):21492–508.
78. Boroujeni MB, Dastjerdeh MS, Shokrgozar M, Rahimi H, Omidinia E. Computational driven molecular dynamics simulation of keratinocyte growth factor
behavior at different pH conditions. Inf Med Unlocked. 2021;23:100514.

Page 15 of 15

79. Prabha G, Raj V. Preparation and characterization of polymer nanocomposites
coated magnetic nanoparticles for drug delivery applications. J Magn Magn
Mater. 2016;408:26–34.
80. Lurie DJ, Mäder K. Monitoring drug delivery processes by EPR andrelated techniques—principles and applications. Adv Drug Deliv Rev.
2005;57(8):1171–90.
81. Reynolds L, Gardecki JA, Frankland SJV, Horng ML, Maroncelli M. Dipole solvation in nondipolar solvents: Experimental studies of reorganization energies
and solvation dynamics. J Phys Chem. 1996;100(24):10337–54.
82. Kamel M, Raissi H, Morsali A. Theoretical study of solvent and cosolvent
effects on the interaction of Flutamide anticancer drug with Carbon nanotube as a drug delivery system. J Mol Liq. 2017;248:490–500.
83. Rahmanzadeh A, Rezvani M, Ganji MD, Moghim MT. Corrosion protection performance of Laurhydrazide N′-propan-3-one (LHP) adsorbed onzinc surface: A DFT-MD simulation investigation. Mater Today Commun.
2023;36:106946.
84. Perveen M, Nazir S, Arshad AW, Khan MI, Shamim M, Ayub K, Iqbal J. Therapeutic potential of graphitic carbon nitride as a drug delivery system forcisplatin (anticancer drug): A DFT approach. Biophys Chem. 2020;267:106461.

Publisher’s NoteSpringer Nature remains neutral with regard to jurisdictional claims inpublished maps and institutional affiliations.