Simulation of nanodrug by theoretical approach

Abstract

In recent years, HIV-1 integrase (IN) has become an attractive target for designing antiretroviral agents. The development of raltegravir and other successful lead IN inhibitors has also influenced the IN inhibitor design strategy. This has led to the identification of several potent inhibitors in these last 2 years. The medicines which have the compound of C-centered and N-centered anti-HIV inhibitor with single-walled carbon nanotube are examined by density functional theory (DFT) method. In this paper, the end of the nanotubes, which was saturated with hydrogen atoms, was examined by DFT at the level of B3LYP and 6-31G(d) standard basis set. There are free Gibbs energy, free Helmholtz energy, enthalpy, bond length (Å), bond angle (in degrees), dihedral angle (in degrees), energy hyperconjugation, total energy (in Kcal mol⁻¹), moment dipole (in Debye), occupancy between nanotube (6, 6), and chalcone derivative. These cases and medicines show that complex 2 is more stable than the other complexes.

Background

Since the discovery of carbon nanotubes by Iijima [1], extensive research has been devoted to their structural characterization [2]. Among the numerous delivery systems currently under investigations, carbon nanotubes (CNTs) seem to embody a promising option [3]. Pristine carbon nanotubes (pCNTs) are made up of carbon atoms arranged in a series of condensed benzene rings and wrapped into a tubular form (Figure 1). Concerning their use in biological systems, lack of solubility (both in organic solvents and aqueous solutions), formation of thick and inhomogeneous bundles, circulation half-life of 3 to 3.5 h [4], and biocompatibility and immunogenicity limitations raise great concerns. However, these observations hold only for pCNTs and, therefore, just indicate the need for further modifications in order to explore the feasibility of functionalized CNTs (f-CNTs) as safe bio-nanomaterial [5, 6]. In particular, the application of f-CNTs as new nanovectors for drug delivery became doable soon after the demonstration of cellular uptake of this new material [7, 8]. It is worth to mention that apart from a few cases of phagocytic incorporation inside macrophages [9, 10] (which are known to be large cleaning cells able to remove foreign material including less soluble nanotubes), no uncoated pCNTs were reported to penetrate inside the cells without displaying remarkable effect. This last point should reinforce the use of f-CNTs as improved, less harmful nanovehicles, especially after our recent discovery regarding the lack of a direct correlation between the kind of functionalization on the surface of carbon nanotubes and the extent of their internalization [11–13]: either electrostatically neutral or charged f-CNTs could be taken up by cells with comparable amount, hence indicating that numerous different chemical procedures could be adapted to introduce several groups and functionalities. Further, an increased understanding of IN structural biology has opened up novel approaches to inhibit IN, such as targeting its multimerization or interaction with cellular cofactors [14]. In the paper, complex between chalcone and nanotube (6, 6) is investigated, and chalcone is used as anti-HIV drug. The chemistry of chalcones has generated intensive scientific studies throughout the world. Special interest has been focused on the synthesis and biodynamic activities of chalcones. The term ‘chalcones’ was given by Kostanecki and Tambor [15]. These compounds are also known as benzalacetophenone or benzylidene acetophenone. In chalcones, two aromatic rings are linked by an aliphatic three carbon chain. Chalcone bears a very good synthon, so a variety of novel heterocycles with good pharmaceutical profile can be designed. Chalcones are α- and β-unsaturated ketones containing the reactive ketoethylenic group CO-CH=CH-. These are colored compounds because of the presence of the chromospheres -CO-CH=CH-, which depend in the presence of other auxochromes. Chalcones resemble the diketo acid functionality and are potential leads in designing potent IN inhibitors. Potent chalcones were identified through an NCI drug screening program [16]. The structures of chalcone are shown in Figure 2.

Figure 1

The optimized complex of chalcone derivative - SWCNT (6, 6) in B3LYP/6-31G(d) method at 298.15K.

Figure 2

The structures of chalcone derivative. Optimizations were performed by B3LYP/6-31G(d) method at 298 K. (a) (Z)-4-(3-fluoro-4-methylbenzylamino)-2-hydroxy-4-oxobut-2-enoic acid. (b) (E)-3-(2-hydroxyphenyl)-1-phenylprop-2-en-1-one. (c) (E)-1-(2, 4-hydroxyphenyl)-3-(2-hydroxyphenyl)prop-2-en-1-one.

Results and discussion

We measured the parameters such as bond length (Å), natural bond orbital (NBO), and bond angle, dihedral angle, distances of analyzed models of the SWCNT (6, 6). The end of the nanotubes, which was saturated with hydrogen atoms, was examined by DFT at the level of B3LYP and 631G(d) standard basis set and is shown in Tables 1, 2, and 3. The electron that is given by the complexes in a reaction should make it as HOMO, while that which captured the complexes must be placed on its LUMO [17], so the atom on which the HOMO mainly scattered should be able to separate the electrons, while the atom, by holding the LUMO, should achieve electrons on this basis. HOMO-LUMO gap is usually associated with chemical stability against electronic excitation with a larger distance like greater stability [18]. The energy (kcal mol⁻¹) and dipole moments (Debye) indicate the consistency among the three complex calculations in the DFT method. The optimized configurations are shown in Figures 1 and 2. In Table 1, it becomes obvious that the complexes 2 and 3 have higher hyperconjugation energy than complex 1. The results also show that as the P increases through the sharing of hybrid atoms, the occupancy decreases. The hybrid s orbital shared in the oxygen atom in complex 3 is more than the hybrid s orbital shared in complexes 1 and 2. Most of the combined energy hyperconjugations are stable. Occupancy coefficient is smaller. Complex 2 is more stable than complexes 1 and 3. The energy hyperconjugation of complex 2 (21.25) is lesser than that of complex3. Reduced coupling energy is due to the resonance interference.

Table 1 The parameters of NBO complexes 1, 2, and 3 by B3LYP/631G(d) method at 298.15 K

Table 2 The parameter of bond distances, bond angles, and torsional angles in B3LYP/631G(d) method optimized complexes 1, 2, and 3 at 298.15 K

Table 3 The parameter of Mulliken charge, energy HOMO/LUMO and gap energy in B3LYP/631G(d) method at 298.15 K

Based on the drug resonance structure, a phenolic ring is observed. In complex 2, the negative charge is located in orthoposition. However, in complex 3, the negative charge is in the oxygen group (OH). Thus, complex 2 is stable. The hybrid orbital S of a compound is lower. The occupancy factor is larger. In complex 2, the hybrid and occupancy are sp^1.88 and 1.9355, respectively.

The calculations of the total energies and energy hyperconjugation (E²) of the optimized structures, dipole moments (μ), occupancy, and hybrid orbital at B3LYP/631G(d) levels are presented in Tables 2 and 3. The DFT calculated geometric parameters for complexes 1, 2, and 3 are compared in Table 2. The bond lengths of C₃₀-O₈₄ calculated for complexes 1, 2, and 3 at the DFT level are 1.383, 1.389, and 1.388 Å, respectively at the B3LYP/631G(d) level. The bond length of C₈₅…C₈₇ for complex 1 is 1.50671 Å; for complexes 2 and 3, 1.41639 and 1.41556 Å, respectively. The bond length of C₈₈… N₉₂ (1.37423 Å) in complex 1 is lower than the bond length of C₈₈=C₉₂ in complexes 2 (1.35015 Å) and 3 (1.34867 Å). This is because the electronegative nitrogen is bigger than carbon. The bond length of C₈₈=O_93/92 in complexes 1 and 2 are 1.22636 and 1.33211 Å respectively lower than those of C=C, C…N in complexes 2, 3, and 1. The dihedral angles of C₁₀₀…C₁₀₃F/O/H₁₀₇¹ for complexes 1, 2, and 3 are 118.48520°, 117.99263°, and 118.85317° (in F, O, and H atoms). In locations 1, 2, 3, 4, 5, and 6, the hydra angle differences are observed in Table 1 and Figure 3. In Table 3, the Mulliken charges in donor electronegative atom O₈₄ and acceptor C₃₀ are negative and positive, respectively. The gap of energy of complex 2 is larger than that of complexes 1 and 3. Therefore, complex 2 is stable (Table 4).

Figure 3

Parameter of dihedral angle change to locations 1, 2, 3, 4, 5, and 6 of complexes 1, 2, and 3 formed in B3LYP/631g( d ) method at 298.15 K.

Table 4 Comparison between stability energy and moment dipole of complexes 1, 2, and 3 formed in B3LYP/631g(d) method at 298.15 K

Conclusions

Based on the above discussion, the following conclusions were made:

● The Mulliken charges of the donor atoms are negative.

● The formed bond between oxygen and carbon is stronger and has more hybrid S orbital sharing, so the bond length becomes shorter.

● There is no reaction between the nanotube and drugs in the normal body temperature.

● NBO analysis shows high hyperconjugations in all compounds.

● By increasing the hybrid P orbital sharing, the occupancy decreases.

Methods

A computer was used to account all calculations, which has Intel® Core™ 2 quad CPU 8400 with 4 GB RAM Gaussian 98 plan package [19] Gauss view, and nanotube model [20] maker at DFT of theory, the B3LYP useful hybrid [21] with the standard of 631G(d) basis set [22, 23]. Schemes were used to display the geometric optimization of the nanotube (6, 6) with 84 atoms and compound chalcones (HIV-1 inhibitors). Separately (Figures 1, 2, and 3) then, complexes 1,2, and 3 were formed. The reaction of the nanotube and chalcone is shown in Equation 1.

$$\begin{array}{l}\mathrm{Chalcone}\\ +\mathrm{Nanotube}\left(6,6\right)\mathrm{Chalcone}-\mathrm{Nanotube}\left(6,6\right)\\ +{\mathrm{H}}_2\end{array}$$

(1)