A DFT, AIM and NBO study of isoniazid drug delivery by MgO nanocage

Accepted Manuscript Full Length Article A DFT, AIM and NBO study of isoniazid drug delivery by MgO nanocage Isa Ravaei, Mojtaba Haghighat, S.M. Azami PII: DOI: Reference:

S0169-4332(18)33071-X https://doi.org/10.1016/j.apsusc.2018.11.005 APSUSC 40850

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Applied Surface Science

Received Date: Revised Date: Accepted Date:

29 August 2018 25 October 2018 1 November 2018

Please cite this article as: I. Ravaei, M. Haghighat, S.M. Azami, A DFT, AIM and NBO study of isoniazid drug delivery by MgO nanocage, Applied Surface Science (2018), doi: https://doi.org/10.1016/j.apsusc.2018.11.005

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Dear Editor: Alfredo Juan Enclosed is a manuscript, entitled "A DFT, AIM and NBO study of isoniazid drug delivery by MgO nanocage ". Please accept it as a candidate for publication in the Applied Surface Science. It is a theoretical drug delivery study on geometric, charge transfer, HOMO/LUMO gap and electronic properties of Isoniazid (INH) drug on pristine and Aldoped MgO nanocage (MgONC). Our calculations showed that the HOMO/LUMO gap of the Al-doped MgONC is significantly changed after the adsorption of INH molecule corresponding to the most stable configuration that gives rise enhance the electrical conductivity of the MgONC. In conclusion, the electronic properties of Al-doped MgONC are strongly sensitive to the presence of INH molecule and therefore it can be used in (bio) sensor devices and can be used to trace the drug via spectrophotometric techniques in the body. I hereby certify that this article is our original unpublished work and it has not been submitted to any other journal for reviews. The article has been written by the stated authors who are all aware of its content and approve its submission. If accepted, the article will not be published elsewhere in the same form, in any language, without the written consent of the publisher.

Best Regards, Isa Ravaei Faculty of Sciences, Yasouj University P.O. Box : 75918-74934, Yasouj, Iran Tel.: (+98) 9102962028 E-mail 1: [email protected] E-mail 2: [email protected]

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A DFT, AIM and NBO study of isoniazid drug delivery by MgO nanocage Isa Ravaei a,*, Mojtaba Haghighatb, S.M Azamia a

Chemistry Department, Faculty of Sciences, Yasouj University, PO Box 75918-74934, Yasouj, Iran b

Behbahan University of Medical Sciences, Behbahan, Iran *Corresponding author. E-mail: [email protected]

Abstract

Density functional theory (DFT), quantum theory of atom in molecule (QTAIM), and natural bond orbital (NBO) have been performed for geometry optimization, binding energy, electronic properties, and adsorption of drug isoniazid (INH) on the pristine and Al-doped Mg12O12 nanocage (MgONC). This drug has tendency to attach via its nitrogen and oxygen atoms to the Mg atoms of the nanocage with adsorption energy in range of -0.96 to -2.58 eV based on the dispersion corrected M062X level of theory. Isoniazid was found to be properly adsorbed on the MgONC while the electronic properties of the MgONC was not significantly changed. But, Al- doped MgONC presents high sensitivity to isoniazid, compared with the pristine nanocage structure, particularly the Al doped one was changed dramatically. The Aldoped MgONC can adsorb isoniazid more strongly with adsorption energy (Eads) equal to 2.58 eV, corresponding to the stable configurations. The QTAIM analysis was investigated for both type’s of structural aspects and electronic properties associated with adsorption processes on the MgO nanocage. Furthermore, NBO analysis indicated a stronger donor– acceptor interactions with INH drug and MgONC. Our calculations showed that the HOMO/LUMO gap of the Al-doped MgONC is significantly changed after the adsorption of INH molecule corresponding to the most stable configuration that gives rise enhance the electrical conductivity of the MgONC. In conclusion, the electronic properties of Al-doped MgONC are strongly sensitive to the presence of INH molecule and therefore it can be used in (bio) sensor devices and can be used to trace the drug via spectrophotometric techniques in the body.

Keywords, magnesium oxide, nanocage, isoniazid, Al-doped magnesium oxide, drug delivery, DFT, AIM, NBO

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1. Introduction

In recent years, nanotechnology plays a defining role in the medical industry for the treatment of cancer and other targeted therapies [1-3]. Nanostructures for drug delivery to affected parts of body is one of the most challenging issues in cancer treatment. Additionally, nanostructured therapeutic carriers have made a great advancements in treatment of intracellular diseases. There is a large body of literature addressing the properties of nanostructures as a promising pulmonary drug delivery system for treatment of tuberculosis [4-6]. Tuberculosis or tubercle bacillus (TB) is one of the most common and deadly infectious diseases caused by mycobacterium tuberculosis. It is estimated that there are about two million deaths occur each year as a result of TB related diseases [7]. Isonicotinylhydrazine (INH), known as isoniazid (Laniazid, Nydrazid), is an organic compound and the first drug in the prevention and treatment of TB [8]. Isoniazid (INH) is used to treat effective TB in 1952 [9]. Due to various potential application such as, unique electrical, mechanical and thermal properties, the search for carbon nanomaterials including carbon nanotubes (CNTs) [10], fullerene and fullerene cages have attracted research interest in the recent years [11-13]. However, this growing interest is being redirected into inorganic nanomaterials as well. Therefore, a considerable number of non-carbons such as boron-nitride (BN) and siliconcarbide (SiC) [14, 15], have been developed and some other ones such as beryllium oxide (BeO) have been reported theoretically [16-18], inorganic nanomaterials have become more attractive to drug delivery as a new class of materials [19, 20]. The properties of metal oxides have been widely studied due to their wide range of electronic, chemical, and physical properties. As an exceptional metal oxides, MgO is one of the most unique materials of such compounds which plays a role in advanced materials design’s development. MgO nanotubes are semiconducting with a gap of about 5.44 eV [21]. Many efforts have been devoted to the study of the physical and chemical properties of MgO clusters [22, 23]. Recently adsorption of some gases such as H2, CH4, C2H4 and CO on MgO nanomaterial have been reported [24-27].

In this research, we have studied the interaction of isoniazid (INH) on electronic properties of pristine and Al- doped magnesium oxide nanocage (MgONC) by using density functional theory (DFT), Quantum Theory Atom in Molecule (QTAIM) and Natural Bond Orbital (NBO). The adsorption energies (Eads), the density of states (DOS) analysis, and the net electron transfers were calculated. We are interested in understanding whether the MgONCs and different pristine and Al-doped MgONCs for the INH drug can act as chemical biosensors. This study may be an incitement experimental efforts for retooling and optimization of INH treatment and human health improvement. The results may provide new insights into the development of drug-carrier of INH for cancer fighting drugs. 3

2. Computational methods

2.1 DFT calculations

In the present investigation, the interaction of isoniazid molecule with a MgO nanocage containing 12 magnesium and 12 oxygen atoms was studied using theoretical techniques. Density functional theory (DFT) calculations were carried out using method employing with the functional of M062X [28]. All the atoms have been described with a 6-311G(d, p) basis set [29] with the contraction scheme implemented in the GAMESS code [30]. GaussSum program has been used to obtain the DOS results [31]. We have defined adsorption energy in the usual way as: Eads = E(Mg12O12 + isoniazid) – E(Mg12O12) – E(isoniazid) + EBSSE

(1)

In this equation Eads is the total energy of an adsorbed, E(Mg12O12 + isoniazid) corresponds to the energy of the MgO nanocage in which isoniazid is adsorbed on the surface, E(MgO) is the energy of the isolated MgO nanocage, E(isoniazid) is the energy of a single isoniazid molecule and EBSSE is the energy of the basis set superposition error. Furthermore, the gap energy (Eg) is defined as follows Eg = ELUMO - EHOMO

(2)

Where ELUMO and EHOMO are energy of HOMO and LUMO. In the open shell systems EHOMO was replaced by ESOMO (SOMO = Singly Occupied Molecular Orbital). When we evaluate the properties of the sensor, the change of Eg defined by ∆Eg = (Eg2 - Eg1)/Eg1 * 100

(3)

Where Eg1 and Eg2 are, the initial values of the Eg and encapsulation complex, respectively. Following equation for the chemical potential (µ) is also obtained by µ = (EHOMO + ELUMO)/2

(4)

According to Koopman’s theorem [32] in order to examine the reactivities, the chemical hardness (η), global softness (S), and electrophilicity index (ω) were calculated using the following equations: (5) (6) (7)

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2.2 Atoms in Molecules (AIM) calculations

Quantum Theory of Atoms in Molecules (QTAIM) [33] is one of the most powerful tools in modern theoretical chemistry and creates a bridge between advanced quantum chemistry and experimental approach. The QTAIM method was used to analyze the electron density and bonding characteristics of the systems [33]. QTAIM analysis of charge density (ρ) and Laplacian of charge density ( ) is performed to describe the nature of the interaction. Other parameters in QTAIM are kinetic energy density (G), and the potential energy density (V). According to this theory, each pair of interacting atoms is linked by the bond path (BP), along which the ρ is maximum with regards to any neighboring line. On the bond path (BP) there is a saddle point, called bond critical point (BCP), and bonds can be characterized via properties evaluated at the BCP. The total electronic energy density (H) of bond critical point (BCP) is defined as [34, 35]: H(r) = G(r) + V(r)

(8)

According to the QTAIM, there are two types of atom-interactions. (1) "Covalent" interactions that is shared and closed-shell interactions (ρ ˃10−1au with ( ) ˂ 0 at the BCP). H(r) at BCP is positive and negative in closed-shell interactions and shared interaction respectively. (2) "Electrostatic" interactions ( au in van der Waals complexes with at the BCP). The nature of interactions for states of is electrostatic, is covalent and partially covalent and partially electrostatic. Furthermore, in the case that, interaction of closed-shell systems: ions, systems having van der Waals interactions or H-bonds and H(r) are positive. The AIM analyses were conducted using AIM 2000 package [36] at M062X/6-311G(d, p) level of theory.

3. Results and discussion 3.1 Optimized Mg12O12

The computed vibrational frequencies are all positive in the range of 102.98 to 775.35 cm-1. The nanocage involves 8 hexagonal and 6 tetragonal rings. Two types of Mg-O bonds can be identified which are shared between 4 and 6 ([4- 6]), 6 and 6 ([6-6]), membered rings, as shown in Figure 1. Where the equilibrium bond length are about 1.93 and 1.87 Å, respectively. Similarly, three types of MgOMg or OMgO angles are distinguished he g angles are larger than the corresponding g g ones he alue of g angles corresponding to the hexagonal, and tetragonal rings is about , , and , respectively. The vibrational frequencies for all of the stationary points calculated and indicating this structure is a true minimum on the potential energy surface.

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The DOS plots (Figure 1) shows that the Mg12O12 are a semiconductor with a HOMO (highest occupied molecular orbital) LUMO (the lowest unoccupied molecular orbital) energy gap (Eg) of 7.56 eV for Mg12O12. Profiles of HOMO and LUMO of the nanocage have been shown in Figure 2 so that HOMOs are mostly contributed from oxygen atoms, and the LUMOs are by magnesium atoms. Depending upon the geometry, one magnesium atom can bind with two or more oxygen atoms. By using Natural Bond Orbital (NBO) population analysis indict about 0.12 |e| electron transfer from the Mg atom to its neighboring oxygen atoms is transfer in the surface of the cluster, which represents the feature polarized of Mg–O bond. The formation of Mg12O12 nanocage is exothermic. In order to determine the stability of the structure, we calculated binding energies using the following formula [18]: Eb =

(9)

Where E(MgO)n and E(MgO) illustrate the total energies of the(MgO) n cluster and a single MgO molecule, respectively. The amount of negative E b shows that the cluster formation is exothermic and stable. The computed binding energy of the MgO cage is -6.73 eV/atom. According to obtained results, it can be concluded that this structure is stable.

3.2 Interaction between isoniazid drug and an individual MgO nanocage and DOS plots

The structure and Molecular Electrostatic Potential (MEP) surfaces of INH drug is shown in Figure 3. According to MEP surfaces, the INH drug presents a more negative value at the N and O atoms. The MEP values for the INH drug predict larger binding energies for the complexes with N or O head of INH than for the ring or C/H head, acting as an electron donor, through the N/O atom, and as an electron acceptor, through the C atom. We focused on INH adsorption to Mg12O12 nanocage surface. For understanding the adsorption behavior of INH molecule on the surface, some pristine nanocage configurations were studied. Therefore, in order to find the best place to adsorb of INH molecule on the surface of MgO system, we tried many initial configuration, such as over the Mg or O atom, above the porous site, tetragonal, and hexagonal rings. In order to obtain the optimal distance, the initial distance between the adsorbent molecule and the nanostructure was sat several times, and finally determined the most stable configuration at the 1.49 to 2.20 Å distances. Eventually, only three relaxed configuration achieved, which are shown in Figure 4 (structures A1 to A3). In addition, electronic properties of these structures are reported in Table 1. For better understanding, we first investigated the most stable structures and then studied the electronic properties of these stable structures. The analysis shows that the adsorption of the -NH2 isoniazid group on Mg atoms is the most favorable interaction between the INH molecules and Mg12O12 nanocage.

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According NBO population analysis, it was found that the INH always acts as a transferor molecule. The magnitude of charge transfer depends upon the direction of the INH molecule toward to the surface. After optimization, all stable complexes have negative value Eads ranging from -1.07 to -1.54 eV (see Table 1), however the adsorption for all, is exothermic. As seen in Figure 4 part A3, most interaction occurred when distance of the NH2 group of the INH molecule from MgONC is about 1.49 Å. The Eads of this process is about -1.54 eV. The mentioned outcomes indicated that the adsorption for A1 – A3 (figure 4) configurations is exothermic. The adsorption of INH molecule on the surface depends upon the direction of the INH drug and the active sites of magnesium oxide nanocage. In order to obtain more details from these study, as listed in Table 1, we calculated chemical potential (μ), chemical hardness (η), global softness (S), and electrophilicity index (ω) for all structures. As compared to pristine MgONC, Eg of INH/MgONC slight decrease and the alues of µ, η, S and ω were changed negligibly. Similarly, we investigated the effect of molecule adsorption on the electronic properties of the MgONC pristine. According to DOS plots (Figure 5) compared to the non-adsorption nanocage (Figure 1), the electronic properties of the nano structure were not considerably altered upon the adsorption analysis.

3.3 The interaction of INH with Al-doped MgO nanocage and DOS plots

In the next step, to modify the electrical and chemical properties of pristine MgO nanocage, magnesium atom of the nanocage was substituted with an Al atom. The optimal geometry and the electronic virtues of Al-doped MgONC (Mg11O12Al) are depicted in figure 6 and Table 2 respectively. Adsorption behavior of INH on the Al-doped MgONC surface for the most stable complexes were investigated. In this regard, INH molecule was located in various heads, such as superior the Al atom or an adjoining oxygen or magnesium atoms, in which the INH molecule are located perpendicular or parallel of any heads to the surface, to detect the optimal structure for the Al-doped MgO nanocage. In order to affirm that the most optimal structure has been achieved, the primary distances between INH and Al-doped MgO nanocage was set several times. As a result, these optimal distances were obtained from 1.81 to 2.04 Å. Eventually, only three optimal configurations with all positive vibrational frequencies were obtained, Figure 7 (models B1, B2 and B3), and their electronic virtues were depicted in Table 2. The Eads for INH adsorption on Al-doped MgO nanocage was calculated to be about -1.97, -0.96 and − 58 eV corresponding to B1, B2 and B3 configurations, respectively. The polar characteristic of Mg-O bond induced electric field around the positively charged Mg which can polarize INH molecule and adsorption it (in other head near the Al- doped), so that the INH prefers to be adsorbed atop a Mg atom (near Al- doped) as compared to oxygen atoms of the nanocage surface. This fact can also be true for Al-O bond. Since aluminum atom has one electron in the P orbital of the valance shell, the electron can easily be transferred to oxygen atoms compared to magnesium atom. 7

Calculated DOS of INH/Al-doped MgONC complexes are shown in Figure 8. Obviously, Eg value corresponding to most stable configuration B3 has been changed remarkably compared to the pristine MgONC. The energy gap Eg (or band gap in bulk materials) is one of the major factor determining the electrical conductivity of a material and there is a classic relation between them as follows [15]: (10) Where σ and K are the electrical conductivity and the Boltzmann’s constant respectively. According to this equation, smaller value of the Eg at a given temperature leads to higher electrical conductivity. Accordingly, the electrical conductivity of MgONC changes with adsorption of INH molecule .The significant change of about 23.67, 37.08 and 47.01 (Table 2) in the HOMO-LUMO gap (Eg) value demonstrates the high sensitivity of the electronic properties of INH drug adsorption on the Al-doped MgONC. According to the calculated DOS, the Al-doped MgONC is a semiconductor with an Eg of 3.15 eV revealing significant changes in electronic properties of MgONC after Al doping. DOS plot of the INH/Al-doped MgONC complexes showed a considerable change of the electronic properties compared to primary Al-doped MgONC, indicating that the electronic properties of the Al-doped MgONC is sensitive to the INH drug adsorption. HOMO-LUMO gap value corresponding to most stable configuration B3 has been increased remarkably to 4.62 eV (by about 47%) compared to the pristine Al-doped MgONC (3.15 eV). These variations in the HOMO-LUMO gap values cause the fluorescence emission after drug interactions with the Al-doped MgO nanocage and it can aid the route of the drug by spectrophotometer in the body. In order to obtain more details from these study, we calculated chemical potential (μ), chemical hardness (η), global softness (S), and electrophilicity index (ω) for all structures of INH/Mg11O12Al complexes, as listed in Table 2. The alues ω of INH/Mg11O12Al are 2.66,  and 2.24 eV, for B1, B2 and B3 complexes, respectively. In comparison to Mg11O12Al, Eg of INH/Mg11O12Al significantly changed and the change of the reactivity parameters are not negligible. Therefore, the Eg and η for INH/Mg11O12Al complexes are in order: B3 B1 B2 but this relationship is reversed for chemical potential and global softness values. The energy gap, chemical hardness, and electrophilicity index of structures decreases with adsorption of INH drug on Al-doped MgONC in comparison of INH/MgONC, but the reverse was found in softness and chemical potential values. The HOMO and LUMO for complexes of INH/MgONC and INH/Al-doped MgONC, are depicted in Figure 9. In INH/MgONC structures (A1, A2 and A3), the orbital density in the LUMO is mainly polarized toward the Mg12O12, while HOMO is polarized away from the Mg12O12. Therefore, in INH/Al-doped MgONC structures, the orbital density in the LUMO is polarized toward the Al atom of Al-doped MgONC, while HOMO which is polarized away from the Mg11O12Al.

3.4 Atoms in Molecules

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The quantum theory of atoms in molecules (QTAIM) [37, 38] is a useful tool for visualizing chemical interactions, including non-covalent ones, such as hydrogen or halogen bonding. Therefore, the application of AIM to our complexes can also be useful to ascertain the INHMg and INH-O or INH-Al interaction topology of Mg12O12 or Al-doped Mg12O12. Molecular graphs of the optimized INH/Mg12O12 and INH/Al-doped Mg12O12complexes are illustrated in Figure 10. According to Table 3, all INH-pristine nanocage bonds corresponding to configuration A1, A2, and A3 have positive values of and H(r), indicating their electrostatic character. For O-Mg (oxygen atom from INH boning to Mg of pristine MgO nanocage) and N-Mg (The nitrogen atom of the isoniazid ring), and N-Mg (nitrogen atom from NH2 agent of isoniazid) bonds, the electron density values are 0.0362, 0.0350 and 0.0275 au for the A1,A2 and A3 complexes, respectively. Moreover, the (O-Mg, N-Mg or N-Mg) positive values of 0.0104, 0.0078 and 0.0058 au for configuration A1, A2, and A3, respectively, indicate that these bonds possess the typical characteristic of closed-shell interactions. The increase in polarization makes this species more efficient for electron excitation as well as for delocalization. The QTAIM is also in consistency with our results, because the Mg atom become more polarized and INH prefers to adsorb Mg atom rather than O atom in nanocage. According to results in Table 3, for INH/Al-doped Mg12O12 complexes including configuration B1, B2, and B3 (Figure 10) the electron density values are 0.0810, 0.0514 and 0.0746 au, respectively. Whereas the values of Laplacian of charge density ( ) are between 0.2844 and 0.5607 a.u. It is claimed that in the case of positive Laplacian of charge density ( ) and H(r) the nature of interaction is electrostatic, whereas in case of positive and negative of H(r) the nature of interaction is partly covalent. Therefore, for B1 and B2 complexes have and H(r) values positive and negative, respectively, which indicate that, the N-Al bond is a polar covalent bond and for B3 complex Laplacian of charge density and H(r) are positive which is illustrative of electrostatic bond for O-Al. The QTAIM is also demonstrated that Al-doped nanocage, the Al atom was more polarized and INH drug prefers to adsorb Al rather than Mg or O atom in nanocage.

3.5 NBO Analyses

NBO population analyses were made to obtain natural atomic charges and the other important complexes properties (Table 4), and the interactions between different parts of molecule (second-order perturbation energies, E2) with high accuracy. In the A1-A3 and B1-B3 structures, the distance between Mg or Al atom from MgO nanocage and nearest atoms from INH are listed in Table 4. The average g… bond length (Mg and O atom corresponding to nanocage and nearest atom of INH drug, respectively) in A1 structures (2.05 Å) are smaller than g…N bond length values in A2 and A3 structures (2.15 and 2.20 Å, respectively). However, in B3 structure, the average Al… bond length (Al and O atom corresponding to nanocage and nearest atom of INH drug, respectively) is smaller than Al…N bond length B1 and B2 (1.86 and 2.04 Å, respectively). 9

NBO population analysis shows the partial charges of Mg atom of MgO nanocage in A1, A2, and A3 complexes are between 0.962 and 1.316 au, smaller than those values for Al atom of Al-doped MgO nanocage in B1, B2, and B3 complexes (1.935-2.009 au). The adsorption energy in INH/Al-doped MgONC is almost higher than the INH/MgONC complexes due to the more polar characteristics of Al-O or Al-N than the Mg-O or Mg-N bond. These results were obtained by NBO analysis, so that the accounted charges on the INH compound were between -0.101 and 0.750 corresponding to most optimal configuration A1-A3 and B1-B3. Except B1 complex, it is revealing that a relatively charge is transferred from the INH drug to the MgONC complexes. The obtained large adsorption energies illustrate that INH is chemisorbed on the MgO nanocage surface. In Table 5 the results of intermolecular interactions, as shown by second order perturbation energies (E2), are reported. To save space, only the highest second order perturbation energies for each structure is shown. The electrons were transferred from the lone pair of the INH (LPINH) to the Rydberg orbital of the Mg or Al (RY*) atom of nanocage with E2 values in the range of 0.37-3.18 kcal/mol. The values of E2 for lone pair of drug INH (LPINH) to the LP* of Mg or Al atom were in the range of 3.74–46.31 kcal/mol, revealing that INH had a stronger interaction with pristine and Al-doped MgO nanocage. According to this data, the interaction for the adsorption of INH/Mg11O12Al are strongest than INH/Mg12O12. Considering the nature of interactions, it was demonstrated that the lone pair of INH’s oxygen or nitrogen atom approximately plays a role of donor and it has more donor property than its magnesium or aluminum atom of MgO nanocage. The doping of Al atom on this structure of MgO nanocage leads to the more suitable. Therefore, this could be concluded that the direct effect of Al doping on this nanocage of interactions leads to the more suitable noncovalent interactions.

4. Conclusion

The INH drug prefers to attach via its N and O atoms to the Mg atoms of the nanocage with adsorption energy in the range of 1.07- -2.58eV based on the dispersion corrected M062X level of theory. AIM calculations have shown the electrostatic character and partial covalent nature correspond to the more stable configuration of pristine and Al-doped MgO nanocage, respectively. NBO calculations indicated that the electrons were transferred from the lone pair of the INH drug (LPINH) to the Rydberg orbital of the Mg or Al atoms (RY* Al or Mg) and from the LPINH to the LP* Mg or Al antibonding orbitals (Mg and Al correspond to pristine and Al-doped MgO nanocage, respectively).

These variations in the HOMOLUMO gap values cause the fluorescence emission after drug interactions with the Al-doped MgO nanocage, that is very sensitive and it can aid the route of the drug by spectrophotometer in the body. 10

REFERENCES ]6[Peer, D., Karp, J.M., Hong, S., Farokhzad, O.C., Margalit, R., Langer, R. Nanocarriers as an emerging platform for cancer therapy. Nature nanotechnology. 2007, 2, 751. ]2[Danhier, F., Feron, O., Préat, V. To exploit the tumor microenvironment: passive and active tumor targeting of nanocarriers for anti-cancer drug delivery. Journal of controlled release. 2010, 148, 13546. ]3[Jana, A., Nguyen, K.T., Li, X., Zhu, P., Tan, N.S., Ågren, H., et al. Perylene-derived singlecomponent organic nanoparticles with tunable emission: Efficient anticancer drug carriers with realtime monitoring of drug release. ACS nano. 2014, 8, 5939-52. ]4[Namiki, Y., Fuchigami, T., Tada, N., Kawamura, R., Matsunuma, S., Kitamoto, Y., et al. Nanomedicine for cancer: lipid-based nanostructures for drug delivery and monitoring. Accounts of chemical research. 2011, 44, 1080-93. ]5[Mendes, R.G., Bachmatiuk, A., Büchner, B., Cuniberti, G., Rümmeli, M.H. Carbon nanostructures as multi-functional drug delivery platforms. Journal of Materials Chemistry B. 2013, 1, 401-28. ]1[Soman, N.R., Lanza, G.M., Heuser, J.M., Schlesinger, P.H., Wickline, S.A. Synthesis and characterization of stable fluorocarbon nanostructures as drug delivery vehicles for cytolytic peptides. Nano letters. 200.1-6636 ,8 ,8 ]7[García-Basteiro, A.L., Brew, J., Williams, B., Borgdorff, M., Cobelens, F. What is the true tuberculosis mortality burden? Differences in estimates by the World Health Organization and the Global Burden of Disease study. International journal of epidemiology. 2018. ]8[Group, T.A.S. A trial of early antiretrovirals and isoniazid preventive therapy in Africa. New England Journal of Medicine. 2015, 373, 808-22. ]9[Bernstein, J., Lott, W.A., Steinberg, B., Yale, H.L. Chemotherapy of experimental tuberculosis. V. Isonicotinic acid hydrazide (nydrazid) and related compounds. American Review of Tuberculosis and Pulmonary Diseases. 1952, 65, 357-64. ]61[Iijima, S. Helical microtubules of graphitic carbon. nature. 1991, 354, 56-8. ]66[Lu, X ,.Chen, Z. Curved pi-conjugation, aromaticity, and the related chemistry of small fullerenes (< C60) and single-walled carbon nanotubes. Chemical reviews. 2005, 105, 3643-96. ]62[Pupysheva, O.V., Farajian, A.A., Yakobson, B.I. Fullerene nanocage capacity for hydrogen storage. Nano Letters. 2007, 8, 767-74. ]63[Oku, T., Narita, I., Nishiwaki, A., Koi, N., Suganuma, K., Hatakeyama, R., et al. Formation, atomic structures and properties of carbon nanocage materials. In: Carbon, Springer, 2006, pp. 187216. ]64[Wolf, S., Edmonds, M., Kummel, A., Nemani, S., Yieh, E. Low-temperature atomic layer deposition of boron nitride and bn structures. Google Patents, 2018. ]65[Branicio, P.S., Zhang, J., Rino, J.P., Nakano, A., Kalia, R.K., Vashishta, P. Plane shock loading on mono-and nano-crystalline silicon carbide. Applied Physics Letters. 2018, 112, 111909. ]61[Beheshtian, J., Ravaei, I. Toxic CO detection by Li-encapsulated fullerene-like BeO. Structural Chemistry. 2018, 29, 231-41. ]67[Ravaei, I., Beheshtian ,J. A DFT Study on Alkali and Alkaline Earth Metal Encapsulated Fullerene-Like BeO Cluster. JOURNAL OF THE KOREAN CHEMICAL SOCIETY-DAEHAN HWAHAK HOE JEE. 2017, 61, 311-9.

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]68[Beheshtian, J., Ravaei, I. Hydrogen storage by BeO nano-cage: A DFT study. Applied Surface Science. 2016, 368, 76-81. ]69[Slowing, I.I., Trewyn, B.G., Giri, S., Lin, V.Y. Mesoporous silica nanoparticles for drug delivery and biosensing applications. Advanced Functional Materials. 2007, 17, 1225-36. ]21[Liang, R., Wei, M., Evans, D.G., Duan, X. Inorganic nanomaterials for bioimaging, targeted drug delivery and therapeutics. Chemical Communications. 2014, 50, 14071-81. ]26[Rad, A.S., Ayub, K. Nonlinear optical, IR and orbital properties of Ni doped MgO nanoclusters: A DFT investigation. Computational and Theoretical Chemistry. 2018. ]22[Javan, M.B. Magnetic properties of Mg12O12 nanocage doped with transition metal atoms (Mn, Fe, Co and Ni): DFT study. Journal of Magnetism and Magnetic Materials. 2015, 385, 138-44. ]23[Li, M., Wang, X., Li, H., Wei, D., Qiu, G., Liu, F., et al. Electrochemical properties of tadpolelike MgO nanobelts. Materials Letters. 2013, 106, 45-8. ]24[Koo, K.Y., Roh, H.-S., Seo, Y.T., Seo, D.J., Yoon, W.L., Park, S.B. Coke study on MgOpromoted Ni/Al 2 O 3 catalyst in combined H 2 O and CO 2 reforming of methane for gas to liquid (GTL) process. Applied Catalysis A: General. 2008, 340, 183-90. ]25[Dohnalek, Z., Kimmel, G.A., Joyce, S.A., Ayotte, P., Smith, R.S., Kay, B.D. Physisorption of CO on the MgO (10 )1Surface. The Journal of Physical Chemistry B. 2001, 105, 3747-51. ]21[Boese, A.D., Sauer, J. Accurate adsorption energies for small molecules on oxide surfaces: CH4/MgO (001) and C2H6/MgO (001). Journal of computational chemistry. 2016, 37, 2374-85. ]27[Gribov, E.N., Bertarione, S., Scarano, D., Lamberti, C., Spoto, G., Zecchina, A. Vibrational and thermodynamic properties of H adsorbed on g in the 00− 0 K inter al he Journal of Physical Chemistry B. 2004, 108, 16174-86. ]28[Hohenstein, E.G ,.Chill, S , Sherrill, C D Assessment of the performance of the 0 − X and 0 − X exchange-correlation functionals for noncovalent interactions in biomolecules. Journal of Chemical Theory and Computation. 2008, 4, 1996-2000. ]29[Snyder, B.E., Vanelderen, P., Bols, M.L., Hallaert, S.D., Böttger, L.H., Ungur, L., et al. The active site of low-temperature methane hydroxylation in iron-containing zeolites. Nature. 2016, 536, 317. ]31[Schmidt, M.W., Baldridge, K.K., Boatz, J.A., Elbert, S.T., Gordon, M.S ,.Jensen, J.H., et al. General atomic and molecular electronic structure system. Journal of computational chemistry. 1993, 14, 1347-63. ]36[ ’Boyle, N GaussSum 00 . ]32[Parr, R.G., Szentpaly, L.v., Liu, S. Electrophilicity index. Journal of the American Chemical Society. 1999, 121, 1922-4. ]33[Bader, R. Atoms in Molecules: A Quantum Theory: Oxford Univ. Press. Oxford, 1990. ]34[Keith, T., Bader, R., Aray, Y. Structural homeomorphism between the electron density and the virial field. International journal of quantum chemistry. 1996, 57, 183-98. ]35[Popelier, P. Quantum molecular similarity. 1. BCP space. The Journal of Physical Chemistry A. 1999, 103, 2883-90. ]31[Biegler-Konig, F., Schonbohm, J., Bayles, D. Software news and updates-AIM2000-A program to analyze and visualize atoms in molecules. John Wiley & Sons Inc 605 THIRD AVE, NEW YORK, NY 10158-0012 USA, 2001, Vol. 22, pp. 545-59. ]37[Matta, C.F., Bader, R.F. Atoms‐ in‐ molecules study of the genetically encoded amino acids. II. Computational study of molecular geometries. Proteins: Structure, Function, and Bioinformatics. 2002, 48, 519-38. ]38[Srivastava, K., Shimpi, M.R., Srivastava, A., Tandon, P., Sinha, K., Velaga, S.P. Vibrational analysis and chemical activity of paracetamol–oxalic acid cocrystal based on monomer and dimer calculations: DFT and AIM approach. RSC Advances. 2016, 6, 10024-37.

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Table 1 Calculated adsorption energy (E ads), HOMO energies (EHOMO), LUMO energies (ELUMO), HOMOLUMO energy gap (Eg) and Reactivity Parameters for bare Mg12O12 and the INH/Mg12O12 complexes in eV. complex

Eads

Mg12O12

EHOMO

µ

ELUMO

Eg

-8.48

-4.70

-0.92

7.56

∆Eg(%)

a

S

3.78

0.26

2.90

A1

-1.29

-8.36

-4.67

-0.99

7.36

2.73

3.78

0.27

2.97

A2

-1.07

-8.02

-4.57

-1.13

6.88

8.89

3.44

0.29

3.04

A3

-1.54

-8.27

-4.71

-1.15

7.11

6.01

3.56

0.28

3.12

a

The change in HOMO-LUMO gap of MgO nanocage after INH ‎adsorption.

13

Table 2 Calculated adsorption energy (Eads), HOMO energies (EHOMO), LUMO energies (E LUMO), HOMOLUMO energy gap (Eg) and Reactivity Parameters for Al-doped MgONC and the INH/Mg11O12Al complexes in eV. complex

Eads

Mg11O12Al

EHOMO

µ

ELUMO

Eg

-4.23

-2.65

-1.08

3.15

∆Eg(%)

S 1.57

0.64

2.23

B1

-1.97

-3.73

-2.53

-1.33

2.40

23.17

1.21

0.83

2.66

B2

-0.96

-3.21

-2.22

-1.23

1.98

37.18

0.99

1.01

2.49

B3

-2.58

-5.53

-3.22

-0.91

4.62

47.16

2.313

0.43

2.24

14

Table 3 Topological parameters (all in atomic units) for the optimized INH/Mg12O12 complexes correspond to configuration A1, A2, and A3 (in Figure 4) and INH/Mg11O12Al complexes correspond to configuration B1, B2, and B3 (in Figure 7) analyzed. complex

interaction

G(r)

V(r)

H(r)

A1

…

g

0.03628

0.27092

0.057314

-0.0469

0.0104

A2

N…

g

0.03508

0.230487

0.049741

-0.0418

0.0078

A3

NH2…

0.02756

0.1673436

0.0359965

-0.0301

0.0058

g

B1

N… Al

0.081077

0.50397

0.13234

-0.0720

-0.006349

B2

NH2… Al

0.051458

0.28443

0.071554

-0.13128

-0.0004

0.074691

0.56073

0.135728

-0.1312

0.0044

B3

… Al

15

Table 4 Important Bond Lengths (in Å) and NBO Atomic Charges (au) for INH and closed atoms INH to complex

bond

Bond Lengths

Charge Mg

Charge Al

Charge O

Charge N

Charge INH

A1

…

g

2.05

1.077

A2

N…

g

2.15

1.361

-0.548

0.677

A3

NH2…

2.20

0.962

-0.507

0.634

g

-0.727

0.750

B1

N… Al

1.86

2.009

-0.825

-0.101

B2

NH2… Al

2.04

1.935

-0.716

0.658

1.81

1.988

B3

… Al

MgO nanocage.

16

-0.887

0.252

Table 5 Most Important Acceptor-Donor Second-Order Perturbation Energies (in kcal/mol) for Interaction of MgO with INH (LP = Lone Pair, RY = Rydberg Orbitals). complex

Interaction LPINH

LP* Mg or Al

Interaction LPINH

RY* Mg or Al

A1

11.46

1.07

A2

24.23

2.12

A3

3.74

0.37

B1

46.31

3.18

B2

40.42

1.86

B3

6.61

0.42

17

Figure 1 Geometrical parameters of Mg12O12 nanocage and its calculated density of state (DOS) plot. Energy and distances are in eV and Å respectively.

18

Figure 2 (a) Shapes of the HOMO and (b) LUMO of the pristine Mg12O12.

19

Figure 3 (a) Optimized structure of C6H7N3O (isoniazid). (b) The calculated molecular electrostatic potential surface (MEP) of the isoniazid. The surfaces are defined by the 0.0004 electrons/ b3 contour of the electronic density. Color ranges, in a.u.: blue, more positive than green, between 0.010 and 0; yellow, between 0 and –0.015; red, more negative than –0.015.

20

Figure 4 Schematic views of the energetically favorable configurations of INH/ Mg12O12 complexes.

21

Figure 5 The DOS plot of isoniazid adsorption structures on Mg12O12 surface

22

23

Figure 6 Geometrical parameters of Al doped Mg12O12 nanocage and its calculated density of state (DOS) plot. As Al-doped MgONC is an open shell system (with an unpaired electron) in its DOS plots, the colors of dark, red and blue designate pristine Mg12O12, spin up and spin down of Mg11O12Al, respectively. Energy and distances are in eV and Å respectively.

24

Figure 7 Schematic views of the energetically favorable configurations of INH/ Mg11O12Al complexes.

25

Figure 8 The DOS plots of isoniazid adsorption on Al-doped MgONC surface. The colors of red and blue designate spin up and spin down of INHMg11O12Al complex, respectively.

26

Figure 9 HOMO (the left panel) and LUMO (the right panel) of more stable INH/MgONC complexes (configuration A1-A3) and INH/Al-doped MgONC complexes (configuration B1-B3).

27

Figure 10 The molecular graph of INH/MgONC complexes (configurations A1-A3) and INH/Aldoped MgONC complexes (configurations B1-B3). Nuclei and bond critical points are represented by big and small spheres small, respectively (red and yellow circles are bond and ring critical points, respectively). The lines are bond paths.

28

Graphical Abstract

29

Highlights 

Isoniazid (INH) drug adsorption on pristine and Al-doped magnesium oxide nanocage (MgONC) investigated by DFT, AIM, and NBO calculations.



To improve the detection of INH on the pristine MgONC, we investigated pristine MgONC by doping with Al atoms.



The (INH) drug shows strong interactions with the Al-doped MgONC, which may Aldoped MgONC used as a bio-sensor for the detection of INH drug.

30