The molecular geometries of glycolic acid conformers (SSC, and AAT), LA, PLGA, and curcumin are optimized using the M06-2X/6–31 + G* method and are shown in Fig. 1. The selected (optimized) bond length values of SSC, LA, and curcumin molecule along with their experimental values are given in Table 1. That is, the bond length values which are significantly deviated from experimental values are given in Table 1. However, all the optimized bond length values of SSC conformer of glycolic acid, LA and curcumin, are given in Table S1 in supporting information. The selected bonds given in Table 1 are C–C, C = C, and C–O bonds. The bond length values of these bonds slightly deviate from the experimental values, the deviation is greater than 0.02 Å. The deviation is due to the artifact of the selected DFT functional. Because earlier Senthilkumar et al. have noted that the DFT functionals have difficulty determining the bonds with electronegative elements [46]. All other bond length values coincide well with the experimental values (Table S1). The calculated glycolic acid SSC conformer bond length values are compared with Blom et al’s experimental data [47]. In the case of lactic acid, the calculated bond length values are compared with Borba et al’s experimental data [48]. Earlier Tsonko et al. have synthesized curcumin crystals and compared their crystal structure with the theoretical values. [49]. Our calculated bond length values of curcumin are compared with Tsonko et al. study. From Table S1, it can be noted that in curcumin, all enol ring structures there are no large differences in the C‒C bond in the skeleton and the C‒O bonds in both experimental and our theoretical calculation values. Our calculations for the curcumin predict C22‒O6 bond is a single bond (1.328 Å), and C21 = O5 is a double bond (1.251 Å), respectively. However, the experimental values are 1.316 for C22‒O6 and 1.312 Å for C21 = O5, respectively (Table 1).
Table 1
Calculated bond length values of Glycolic acid (SSC) conformer, Lactic acid (LA) and Curcumin using M06-2X/6–31 + G*, and compared with the available experimental data.
SSC |
Bonds | M06-2X | Exp.a |
C1–C2 | 1.512 | 1.495 |
C1‒O6 | 1.398 | 1.406 |
C2 = O5 | 1.208 | 1.210 |
C2–O8 | 1.339 | 1.349 |
LA |
C4 − O1 | 1.404 | 1.425 |
C4 − C5 | 1.525 | 1.521 |
C4 − C6 | 1.518 | 1.519 |
C6 − O2 | 1.340 | 1.320 |
C6 − O3 | 1.209 | 1.208 |
C6 − C4 | 1.518 | 1.519 |
curcumin |
C19 = C23 | 1.343 | 1.348 |
C20 = C24 | 1.345 | 1.348 |
C21 − O5 | 1.251 | 1.312 |
C22 − O6 | 1.328 | 1.316 |
C21 − C23 | 1.476 | 1.450 |
C22 − C24 | 1.457 | 1.450 |
C21 − C25 | 1.444 | 1.392 |
C22 = C25 | 1.374 | 1.403 |
C21 − C23 | 1.476 | 1.450 |
C21 − C25 | 1.444 | 1.392 |
C22 − C25 | 1.374 | 1.403 |
C26 − O1 | 1.414 | 1.440 |
C27 − O2 | 1.415 | 1.440 |
aExperimental values are taken from Ref No:[47] for SSC, Ref No:[48] for LA, Ref No:[49] for curcumin. |
The energetical parameters of SSC, AAT, LA, PLGA, and curcumin are given in Table 2. Among the SSC and AAT conformers, SSC is energetically more stable than AAT conformers. However, AAT is highly polar i.e. AAT has a larger dipole moment than SSC conformer. Further, the chemical hardness, chemical potential, of curcumin are comparably lower than other studied systems. The condensed Fukui functions of selected atoms i.e. most favorable sites of curcumin are given in Table 3. The condensed Fukui functions of all the atoms of curcumin are given in Table S2. In general, the condensed Fukui function is used to explain the reactivity of the particular site of any chemical system. Earlier the molecular selectivity of the site was first analyzed by Parr and Yang [50] using local reactivity descriptors, in particular, Fukui functions. More recently, Mohamed et al. have performed docking studies of Dihydrothiouracil-Indenopyridopyrimidines with Human-DNA Topoisomerase II using theoretical methods [51]. They have determined the electrophilic as well as nucleophilic sites using condensed Fukui functions. Therefore, condensed Fukui functions can be used to predict the favorable reactive sites of any given molecule. In the present study, the Fukui function indices and Dual descriptor [52] are calculated using M06-2X/6–31 + G* and are given in Table 3. From Table 3, it can be noted that the C21 and C22 site is the most electrophilic active site in curcumin. Similarly, the active nucleophilic sites are O5 and O6 in curcumin. This is because the presence of O5 and O6 are attached to the C21 and C22 atoms respectively, Similarly, the same conclusion is derived from Dual descriptor ∆f regarding electrophilic and nucleophilic attacks respectively.
Table 2
Calculated Total energy (E, hartree), dipole moment (µm, Debye), chemical hardness (η, eV), and chemical potential (µ, eV) of glycolic acid (SSC and AAT), LA, PLGA and curcumin using the M06-2X/6–31 + G* method.
| E | µm | η | µ |
SSC | -304.17966 | 2.45 | 5.01 | -4.91 |
AAT | -304.17420 | 4.65 | 4.69 | -4.87 |
LA | -343.47905 | 2.42 | 4.95 | -4.81 |
PLGA | -571.26298 | 2.19 | 5.03 | -4.90 |
curcumin | -1263.09165 | 2.19 | 2.62 | -4.25 |
Table 3
Calculated condensed Fukui functions values of selected atoms of curcumin using the M06-2X/6–31 + G* method.
| f+ | f0 | f− | ∆f |
O5 | -0.215 | -0.732 | -0.841 | 0.626 |
O6 | -0.703 | -0.827 | -0.876 | 0.172 |
C21 | 0.743 | 0.554 | 0.726 | -0.162 |
C22 | 0.728 | -0.453 | 0.505 | -0.069 |
The energetical parameters of Cur-SSC, Cur-AAT, Cur-LA, and Cur-PLGA complexes are calculated using the M06-2X/6–31 + G* method. The energetical parameters such as total energy, interaction energy, and energy gap (HOMO-LUMO gap) and reactivity parameters such as chemical hardness and chemical potential are calculated and are given in Table 4. The sum of NBO charges of each molecule in Cur-PLGA complexes is given in Table 5. The detailed NBO charges of Cur-PLGA complexes are given in Table S3. From Table 5, it can be seen that among the studied complexes, large charge transfer is noted in Cur-AAT and Cur-LA complexes. For example, after the interaction, curcumin becomes slightly positive (0.029 e) and AAT becomes negative (-0.029e). That is more negative charges are localized in AAT. A similar trend is observed in the Cur-LA complex. The optimized structures of Cur-SSC, Cur-AAT, Cur-LA, and Cur-PLGA complexes are given in Fig. 2 using the M06-2X/6–31 + G* method. The total energy and dipole moment values of each complex are mentioned in Table 4. From Fig. 2 and Table 4 it can be seen that Cur-AAT is energetically more stable than the Cur-SSC complex. This is due to the formation of inter-and intramolecular H–bond interactions in curcumin as well as the AAT conformer of glycolic acid. In the case of dipole moment values, all the complexes predict similar values except Cur-AAT and Cur-PLGA complexes. The dipole moment values increases in the order of Cur-SSC > Cur-LA > Cur-PLGA > Cur-AAT. This indicates that Cur-AAT and Cur-PLGA complexes are highly polar than the other two studied complexes. That is, Cur-AAT and Cur-PLGA complexes could be highly stable in the liquid phase because of the larger dipole moment. The chemical hardness, chemical potential, and HL gap values predict a similar result in all the complexes considered in this study. Further, a large interaction energy value is noted for the Cur-AAT complex (-17.83 kcal/mol). The interaction energy value increases in the order of Cur-LA > Cur-SSC > Cur-PLGA > Cur-AAT. This trend is in agreement with dipole moment order. However, there is a slight change in the order between Cur-LA and Cur-SSC in the case of dipole moment and interaction energy. The large dipole moment and interaction energy value of the Cur-AAT complex is due to the presence of strong intra- and intermolecular H-bond interactions. Earlier Karataş et al. have concluded that curcumin has a stronger interaction with PLGA, and PLGA can be used as a carrier for drug delivery systems [26]. In the present study, it can be noted that glycolic acid conformers have strong interaction with curcumin, because of this reason glycolic acid is in a polymeric form, and its copolymers for ex. PLGA is used as a carrier for drug delivery systems. In addition to this, polyglycolic acid and its copolymers are also used as a material for synthesizing absorbable sultures in the biomedical field.
Table 4
Calculated Total energy (E, in hartree), dipole moment (µm, in Debye), chemical hardness (η, in eV) chemical potential (µ, in eV and Interaction energy (Eint, in kcal/mol) of glycolic acid (GA-SSC and GA-AAT), LA, PLGA and curcumin using M06-2X/6–31 + G* level of theory.
| E | µm | η | µ | Eint |
Cur-SSC | -1567.28644 | 1.94 | 2.59 | -4.19 | -9.49 |
Cur-AAT | -1567.29426 | 5.86 | 2.44 | -4.53 | -17.83 |
Cur-LA | -1606.58540 | 2.27 | 2.55 | -4.37 | -9.23 |
Cur-PLGA | -1834.37838 | 4.51 | 2.58 | -4.31 | -14.91 |
Table 5
Natural bond orbital (NBO) charges (in e) of Cur-complexes calculated at M06-2X/6–31 + G* method.
Cur-complexes | q |
Cur-SSC | SSC | 0.001 |
Cur | -0.001 |
Cur-AAT | AAT | -0.021 |
Cur | 0.021 |
Cur-LA | LA | -0.029 |
Cur | 0.029 |
Cur-PLGA | PLGA | 0.008 |
Cur | -0.008 |
To get more detailed information about the covalent and noncovalent interactions on the stability of Cur-PLGA complex as well as Cur-SSC, Cur-AAT, and Cur-LA complexes, NBO and QTAIM analysis are performed. The QTAIM theory is one of the useful methods to get an insight into a region of the system. It is used to predict the strength of the covalent and noncovalent interactions in the given system. The Bond Critical Points (BCP) are used to recognize the chemical bonds and strength between atoms.. The AIM analysis of curcumin and Cur-PLGA complexes are performed by using the M06-2X/6–31 + G* method. The topological, and energy parameters for Cur-PLGA complexes are listed in Table 6. The electron density (ρ) and Laplacian of electron density (∇2ρ) values from our AIM analysis is confirmed that the formation of intramolecular H‒bond in AAT conformer between O53···H56‒O55 (Table 4). Apart from O53···H56‒O55, all other interactions mentioned in Table 6 are van der Waals interactions. The H‒bond energy value for the Cur-AAT complex is -9.29 kcal/mol. Earlier studies have shown that the moderate H‒bond energy is ~ -10 kcal/mol [53]. This indicates that the Cur-AAT complex possesses strong intermolecular and intramolecular interactions. This is the reason behind the higher stability of the Cur-AAT complex. There are three intramolecular H-bond interactions were present in the curcumin molecule namely O1···H28‒O3, O2···H29‒O4, and O5···H30 respectively. From Table 6 we can justify that the intramolecular H-bond energy (O5···H30) of pure curcumin (-6.045 kcal/mol) is reduced in Cur-SSC (-5.819 kcal/mol), Cur-AAT (-5.868 kcal/mol)), Cur-LA (-5.849 kcal/mol) and Cur-PLGA (-5.867 kcal/mol) respectively. This is reduced due to the formation of curcumin with SSC, AAT, LA, and PLGA complexes.
Table 6
Calculated bond length (Rv, in Å), topological parameters: the electron density (ρBCP, in a.u.) and Laplacian electron density (∇2ρBCP, in a.u.), energetic parameters: electron kinetic energy density (GBCP, in a.u), electron potential energy density (VBCP, in a.u), total electron energy density (HBCP, in a.u) of the Bond critical point (BCPs), hydrogen bond energy (EHB, in eV) and reduced gradient density (RDG or s(r), in a.u.) of the Cur and Cur-complexes using M06-2X/6–31 + G* method.
Complex | Interaction | Rv | ρBCP | ∇2ρBC | GBCP | VBCP | HBCP | EHB | s(r) |
Cur | O1···H28 − O3 | 2.079 | 0.548 | 1.752 | 0.475 | -0.511 | -0.037 | -16.041 | 0.100 |
O2···H29 − O4 | 2.083 | 0.202 | 0.893 | 0.207 | -0.191 | 0.016 | -5.992 | 0.103 |
O5···H30 | 1.636 | 0.203 | 0.897 | 0.208 | -0.193 | 0.016 | -6.045 | 0.198 |
Cur-SSC | O1···H28 − O3 | 2.096 | 0.020 | 0.088 | 0.020 | -0.019 | 0.002 | -5.854 | 0.040 |
O2···H29 − O4 | 2.088 | 0.020 | 0.089 | 0.021 | -0.019 | 0.002 | -5.963 | 0.041 |
O5···H30 | 1.645 | 0.054 | 0.172 | 0.047 | -0.050 | -0.004 | -15.727 | 0.185 |
O6···H56 − O55 | 3.020 | 0.005 | 0.018 | 0.004 | -0.004 | 0.000 | -1.153 | 0.011 |
Cur-AAT | O1···H28 − O3 | 2.095 | 0.516 | 1.676 | 0.449 | -0.480 | -0.030 | -15.054 | 0.100 |
O2···H29 − O4 | 2.099 | 0.196 | 0.874 | 0.202 | -0.185 | 0.017 | -5.809 | 0.250 |
O5···H30 | 1.661 | 0.198 | 0.879 | 0.203 | -0.187 | 0.016 | -5.868 | 0.124 |
O53···H56 − O55 | 1.908 | 0.316 | 1.134 | 0.290 | -0.296 | -0.006 | -9.289 | 0.064 |
O5···H54 − O53 | 1.750 | 0.368 | 1.362 | 0.339 | -0.338 | 0.001 | -10.608 | 0.048 |
O52···H31 − C13 | 2.475 | 0.099 | 0.359 | 0.080 | -0.070 | 0.010 | -2.193 | 0.037 |
O55···H31 − C13 | 2.505 | 0.091 | 0.359 | 0.079 | -0.068 | 0.011 | -2.125 | 0.039 |
Cur-LA | O1···H28 − O3 | 2.096 | 0.489 | 1.613 | 0.428 | -0.452 | -0.024 | -14.191 | 0.028 |
O2···H29 − O4 | 2.097 | 0.197 | 0.882 | 0.203 | -0.186 | 0.017 | -5.838 | 0.144 |
O5···H30 | 1.683 | 0.197 | 0.882 | 0.203 | -0.186 | 0.017 | -5.849 | 0.124 |
O48 − H58···O5 | 2.019 | 0.218 | 0.796 | 0.198 | -0.197 | 0.001 | -6.166 | 0.078 |
C19 − H37···O48 | 2.322 | 0.137 | 0.460 | 0.111 | -0.108 | 0.004 | -3.379 | 0.099 |
Cur-PLGA | O1···H28 − O3 | 2.094 | 0.550 | 1.745 | 0.474 | -0.511 | -0.038 | -16.048 | 0.100 |
O2···H29 − O4 | 2.099 | 0.197 | 0.881 | 0.203 | -0.186 | 0.017 | -5.828 | 0.119 |
O5···H30 | 1.636 | 0.198 | 0.883 | 0.204 | -0.187 | 0.017 | -5.867 | 0.076 |
O50···H33 − C15 | 2.337 | 0.124 | 0.430 | 0.102 | -0.097 | 0.005 | -3.058 | 0.067 |
Bonding and nonbonding interactions interplay in the Cur-PLGA complexes. Hence it is difficult to understand the functionality of these complexes. The bonding and nonbonding interactions in Cur-PLGA complexes are described by combining Bader’s QTAIM analysis with the noncovalent interaction (NCI) index [54]. The 2D NCI scatter plots of RDG for curcumin are shown in Fig. 3. Figures 4 (a), 4 (b), 5 (a), and 5(b) show that the 2D NCI scatter plots of RDG for Cur-SSC, Cur-AAT, Cur-LA, and Cur-PLGA complexes respectively. In general, the 2D NCI scatter plots of RDG will give a clear picture of the noncovalent interactions in the Cur-PLGA complexes. From Fig. 4(b) it is seen that the Cur-AAT complex is having intramolecular H–bonds in both curcumin as well as in AAT. The peaks at sign(λ2)ρ(r) ≃ −0.03 a.u. in each scatter plot indicates that the presence of conventional H-bonds in curcumin(O5···H30) and in Cu-AAT (O5···H54‒O53) complex. There are no intramolecular H-bonds that exist in all other studied systems, i.e curcumin with SSC, LA, and PLGA complexes. Recently, Nkungli et al. have studied the interaction between iron(III) protoporphyrin IX and 4-methoxyacetophenone thiosemicarbazone theoretical studies [55]. Their NCI index values indicate that the formation of van der Waals interaction in the studied system.
The natural bond orbital (NBO) analysis is one of the best quantum chemical tools to determine the strength of non-covalent interactions as well as the stabilization energy of the interaction between donor and acceptor region [56]. In particular, the stabilization energy predicts the delocalization of electron density in donor-acceptor interaction. In the present study, the stabilization energy E(2) is calculated by using the second-order perturbation theory. The E(2) values for the Cur-SSC, Cur-AAT, Cur-LA, and Cur-PLGA are given in Table 7. The H-bond stabilization energy value for Cur-AAT (LP (1) O53 →BD* (1) O55 – H56) is 4.08 kcal/mol. The new H–bond is formed between Cur-AAT complexes with the highest stabilization energy value. The H–bond stabilization energy value for Cur-AAT (LP (1) O5 →BD* (1) H54-O53) is 14.36 kcal/mol. From Table 4 in all complexes LP (1) O5→LP* (1) H30 having a higher stabilization value. This clearly explains that the curcumin is having strong intramolecular H–bonding interactions. In Cur-LA complexes the H-bond stabilization energy value (LP (1) O5 →LP* (1) H30) is 11.79 kcal/mol. From the NBO analysis, it is noted that there is a transfer of electrons from curcumin to AAT, curcumin to LA, and curcumin to PLGA takes place. That is electrons are transferred from the lone pair orbital of curcumin to the anti-lone pair orbital of AAT, LA, and PLGA respectively. In summary, from AIM and NBO studies, it is concluded that the interaction in curcumin and Cur-SSC, Cur-AAT, Cur-LA, Cur-PLGA complexes are found to be van der Waals in nature.
Table 7
Calculated van der Waals bond length (Rv, in Å), Donor–Acceptor Interactions in the NBO Basis, and Their Second-Order Perturbation Stabilization Energies (E(2), in kcal/mol) of Cur and Cur-complexes using M06-2X/6–31 + G* method.
| Interaction | Donor (i) | Acceptor (j) | Rv | E(2) | E(j)-E(i) | F(i, j) |
Cur | O1···H28 − O3 | LP (1) O1 | BD* (1) O3 − H28 | 2.079 | 3.52 | 1.17 | 0.058 |
O2···H29 − O4 | LP (1) O2 | BD* (1) O4 − H29 | 2.083 | 3.48 | 1.16 | 0.057 |
O5···H30 | LP (1) O5 | LP* (1) H30 | 1.636 | 6.55 | 0.95 | 0.079 |
Cur-SSC | O1···H28 − O3 | LP (1) O1 | BD* (1) O3 − H28 | 2.096 | 3.1 | 1.23 | 0.056 |
O2···H29 − O4 | LP (1) O2 | BD* (1) O4 − H29 | 2.088 | 4.550 | 0.84 | 0.056 |
O5···H30 | LP (1) O5 | LP* (1) H30 | 1.645 | 6.56 | 0.94 | 0.079 |
Cur-AAT | O1···H28 − O3 | LP (1) O1 | BD* (1) O3 − H28 | 2.095 | 3.37 | 1.16 | 0.056 |
O2···H29 − O4 | LP (1) O2 | BD* (1) O4 − H29 | 2.099 | 2.79 | 1.18 | 0.052 |
O5···H30 | LP (1) O5 | LP* (1) H30 | 1.661 | 7.58 | 0.99 | 0.086 |
O5···H54 − O53 | LP (1) O5 | BD* (1) O53 − H54 | 1.750 | 14.36 | 0.77 | 0.094 |
O53···H56 − O55 | LP (1) O53 | BD* (1) O55 − H56 | 1.912 | 4.08 | 1.00 | 0.057 |
O52···H31 − C13 | LP (1) O52 | BD* (1) C13 − H31 | 2.475 | 0.16 | 1.36 | 0.013 |
O55···H31 − C13 | LP (2) O55 | BD* (1) C13 − H31 | 2.505 | 0.53 | 0.99 | 0.021 |
Cur-LA | O1···H28 − O3 | LP (1) O1 | BD* (1) O3 − H28 | 2.096 | 2.2 | 1.14 | 0.045 |
O5···H30 | LP (1) O5 | LP* (1) H30 | 1.683 | 11.79 | 1.02 | 0.109 |
Cur-PLGA | O1···H28 − O3 | LP (1) O1 | BD* (1) O3 − H28 | 2.094 | 3.33 | 1.16 | 0.056 |
O2···H29 − O4 | LP (1) O2 | BD* (1) O4 − H29 | 2.099 | 3.26 | 1.16 | 0.055 |
O5···H30 | LP (1) O5 | LP* (1) H30 | 1.636 | 6.31 | 0.96 | 0.078 |
O50···H33 − C15 | LP (1) O50 | BD* (1) C15 − H33 | 2.337 | 0.61 | 1.29 | 0.025 |
The antimicrobial activity of any molecule depends on the LUMO energy and density of the molecule. Molecules with lower LUMO orbitals (energy) can accept more electrons than the molecules with higher LUMO orbitals (energy). This indicates higher antimicrobial activity. The molecular density is the molecular mass per unit volume. The activity of the molecule depends upon the molecular density only. If it is negative the molecule is compact and it will reduce the density of the molecule [57]. The LUMO energy and molecular density values are given in Table 8. From Table 8 and Fig. 6, it can be seen that the energy of the LUMO corresponding to the Cur-SSC, Cur-AAT, Cur-LA, and Cur-PLGA complexes is found to be increased in the range of 0.09–0.45 eV. Whereas, the density of the Cur-SSC, Cur-AAT, and Cur-PLGA complexes is increased in the range of 0.04–0.30 amu/A3 respectively. But in the case of the Cur-LA complex, the density is found to be decreased by 0.07 amu/A3. The volume of the Cur-LA is somewhat high (375.92 A3) compared with the other Cur-PLGA complexes. The Cur-PLGA complex shows lower LUMO energy and density values than the other studied systems. This indicates that the Cur-PLGA complex shows higher antimicrobial activity than the other complexes studied. The Cur-LA complex gives a major contribution to increasing the antimicrobial activity of the Cur-PLGA complex. A similar trend is observed in an earlier study also. Recently, Mary et al. have studied the antimicrobial properties of the chalcone-based Schiff bases using the theoretical method [31]. They found that the HL(1–3)-Cu2+ complexes have lower LUMO energy and density. They concluded that the HL(1–3)-Cu2+ complex shows higher antimicrobial activity than the other studied complexes.
Table 8
LUMO energy (in eV) and density (mass/volume, in amu/A3) of Cur and Cur-PLGA complexes calculated at M06-2X/6–31 + G* method.
| LUMO | mass | volume | Density |
Cur | -1.64 | 368.13 | 286.11 | 1.29 |
Cur-SSC | -1.74 | 444.14 | 334.73 | 1.33 |
Cur-AAT | -2.09 | 444.14 | 315.69 | 1.41 |
Cur-LA | -1.81 | 458.16 | 375.92 | 1.22 |
Cur-PLGA | -1.72 | 516.16 | 324.57 | 1.59 |