Spectroscopic and an active site analysis of 2,2-diphenyl-1,3- propanediol as antitumor and inflammatory potential

doi:10.21203/rs.3.rs-3412284/v1

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Spectroscopic and an active site analysis of 2,2-diphenyl-1,3- propanediol as antitumor and inflammatory potential

https://doi.org/10.21203/rs.3.rs-3412284/v1

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published 29 Jan, 2024

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The compound 2,2-Diphenyl-1,3-Propanediol (22D13P) is very useful in the development of biological-based plastic materials. The FT-IR, ¹³C and ¹H-NMR spectra of 22D13P molecule was recorded theoretically as well as compared with experimental results. The fundamental vibrational modes were assigned based on potential energy distribution% (PED%) analysis. The stabilization energy and charge distributions of 22D13P molecule were obtained with the help of natural bond orbital (NBO) analysis. In addition, the electronic properties of 22D13P molecule were analyzed via highest occupied molecular orbital (HOMO) and lowest unoccupied molecular orbital (LUMO). The drug-likeness properties of 22D13P molecule were studied. Furthermore, molecular docking was used to examine the interactions between the 22D13P molecule and 6I65 receptor from estrogen-related receptor (ER) family. The molecular dynamics simulation analysis showed that 22D13P molecule can be a potential inhibitor for breast cancer treatment.

MEP

HOMO-LUMO

Molecular Docking

Molecular Dynamics Simulation

Drug-likeness

2,2-Diphenyl-1,3-Propanediol (22D13P) compound is an important chemical intermediate that is widely used as a bifunctional organic compound for the production of polymer materials such as polyether, polyurethane, polyesters and as a monomer for polycondensations. 1,3-Propanediols was used as monomers of polypropylene terephthalate fibers [1–3]. The demand for 1,3-Propanediol has been increasing rapidly on a global scale and has an annual market over 100 million pounds [4]. The production of 1,3-Propanediol was mainly for biological fermentation [5–7] or chemical synthesis [8–11]. The development of industrial production for 1,3-Propanediol through this process is limited, as biological fermentation has many negative consequences, such as high cost, complex procedures, and undesirable by-products [12, 13].

Basically, 1,3-Propanediol is produced in low quantities by the medium in which it is synthesized, so removing other components such as cells, proteins, salts, organic acids, and alcohols it increases the overall cost of purification for the targeted compound. Moreover, the price and accessibility of 1,3-Propanediol raw materials are always dependent on non-renewable petroleum resources. Consequently, it was the enormous importance to utilize a sustainable development plan for 1,3-Propanediol production. Obtaining the high-purity bio-based 1,3-Propanediol needed for sophisticated industrial usage was a difficult procedure, despite the fact that producing it through biosynthesis from renewable sources was more advantageous environmentally and economically than chemical synthesis [14, 15].

22D13P molecule is an organic compound used in the synthesis of bio-based polymers with C₁₅H₁₆O₂ molecular formula. The 1,3-Propanediol main body is combined with two phenyl rings to create this molecule 22D13P. In this study, the C₁₅H₁₆O₂ molecule was characterized with the help of density functional theory (DFT) at B3LYP level with the basis set 6-311 + + G(d,p) and compare the obtained data with experimental data from the literature. The structural, spectroscopic and electronic properties of 22D13P molecule were examined for the contribution of future related studies with synthesizing its derivatives. The results of FT-IR spectrum were compared with the experimental values on the Spectral Database for Organic Compounds (SDBS) web page [16] and the fundamental assignments were prepared according to their PED%. The molecular orbital analysis was performed (HOMO-LUMO) to determine the local reactivity descriptors like chemical hardness, softness, chemical potential and electrophilic index. An NBO analysis was also obtained to understand the regions of displacements of the charges that take place within the molecule.

Further, the drug-similarity properties of 22D13P molecule were investigated according to the Lipinski criteria. In addition, with the help of the Swiss Target Prediction tool. This accurately predicts the targets for bioactive molecules based on the combinations of 2D and 3D similarity measurements with known ligand [16, 17], the target receptors with our bioactive molecule interactions were determined. As a result of virtual scanning, it was determined that 22D13P molecule can interact with estrogen receptor (ER) family. Estrogen and estrogen related receptors (ERR) play a very important role in efficient protein synthesis of female phenotype. Irregularities in ERR functions are the cause of some diseases, such as estrogen insensitivity syndrome (EIS) and breast cancer. Blocking estrogen receptors greatly inhibits the growth of breast cancer. Therefore, the discovery of compounds that can interact with estrogen receptors and that can be used as drugs that slow down or block their proliferation is of great importance. The biological activity between 22D13P compound and their target protein was analyzed by the molecular docking study. Furthermore, the molecular dynamics (MD) simulation was performed to find out the stability of 22D13P compound in the active site of estrogen related receptor gamma (ERRγ).

Quantum chemical and spectroscopic calculations

The experimental data of the NMR and infrared spectra of 22D13P molecule were taken from the SDBS web page [16]. The FT-IR spectrum was recorded in spectrometer (FT-IR spectrum one) at 4000 to 4500 cm^− 1. Quantum chemical calculation techniques were used in the Gaussian09W [18] package programme to compute theoretical calculations for structural, spectroscopic, and electronic characteristics. The calculations were performed at the B3LYP level of the density functional theory (DFT) using the

6-311 + + G(d,p) basis set containing diffused and polarized functions. The optimization was performed to determine the most stable structure of the 22D13P molecule and the vibrational frequencies were obtained using the same basis set. The Veda4 [19] software programme assigned the molecules' vibrational frequencies in accordance with their PED analysis. In addition, the analysis of the HOMO-LUMO orbitals of the molecule was carried out. On the other hand, NBO analysis was performed with the help of the NBO 3.1 program, which is included in Gaussian 09W software [18].

Molecular docking analysis

The Brookhaven Protein Data Bank (PDB Code: 6I65) was applied to extract the whole structure of the human estrogen receptor gamma (ERR) [20]. It involved the removal of the ligand molecule, water molecules, and ions. The protein molecule was modified using the AutoDockTools to include hydrogen atoms and kollman charges, and it was then saved in the pdbqt format [21]. A grid box was created with an equal number of grid points (50, 50, 50) using grid space 0.375, and it was stored as a gpf file (grid parameter file) in order to study the binding modes of the protein molecule. Molecular docking was carried out using the Lamarckian genetic algorithm (LGA) with a maximum of 25,00,000 energy assessments, 27,000 generations, and 150 population size, and the results were stored in a dpf file (docking parameter file) [22]. The log file (.dlg) is used to extract the docking parameters and binding energies for the 10 conformers. The optimal conformer was chosen after ranking the binding energies of each ligand's 10 conformers according to the complex's intermolecular interactions and binding energies. Further the molecular dynamics has been performed up to 50 ns to understand the stability of the molecule in the active site of ERRγ. Using the discovery studio visualize programme [23], the intermolecular interactions (hydrogen bonds, hydrophobic interactions, and - interactions) were examined. The optimized molecule was employed in the molecular docking analysis. In addition, the Gasteiger charges and number of rotational torsion angles were estimated via AutoDockTools and it was stored as pdbqt format.

Molecular dynamics simulation

The best conformer was selected from the molecular docking and it was used to perform molecular dynamics simulation. The leap module was used to prepare the topological and coordinate files of the protein and ligand molecule with AMBER ff14SB and GAFF (general AMBER force filed) force filed respectively [24]. With the help of the general AMBER force field (GAFF) and AM1-BCC technique, the antechamber module was utilized to build the topological and coordinates files of the ligand molecule [25]. The complex was solvated using orthorhombic TIP3P water box with the dimensions of 10×10×10Å [26]. The system was minimized using 10,000 steps with steepest descent and conjugate gradient methods with restraints of water model. The whole system was minimized using 10,000 steps without restraints using steepest and conjugate gradient methods. Using an NVT ensemble, annealing was done from 0 to 300 K during a 500-ps period. Then, an isothermal-isobaric (NPT) ensemble was used to equilibrate the material at 300 K and 1 bar of pressure. Further, the final production step was continued up to 50 ns using Langevin thermostat and Berendsen barostat with 2 fs time step [27, 28]. The CPPTRAJ module was used to analyze the MD trajectory files [29] available in the AMBERTOOLS14 package. The bonds involving hydrogen’s were constrained by the SHAKE algorithm [30].

Molecular structure features

The most stable shape of the molecules must be identified as the first stage in a theoretical investigation. Accuracy of the calculations in the next steps is possible by correctly finding the geometry in which the molecule is most stable [31, 32]. In this section, 22D13P molecule was optimized with the DFT/B3LYP level and the 6-311 + + G(d,p) basis set to calculate their structural, spectroscopic and electronic properties. The molecular structure of the compound has C₁ point group symmetry. The optimized geometry of the compound and structural parameters of this structure; such as, bond length and bond angles were presented in Fig. 1 and Table 1 respectively. As per the results, the minimum energy value for the optimized structure of the 22D13P compound was − 731.86 a.u.

Table 1

Selected optimized structural parameters of 22D13P molecule.
Bond Length (Å)	Calculated	Exp.^*	Bond Angle (º)	Calculated	Exp.^*
C₂₃-C₂₄	1.560	1.52	H₃₁-O₃₀-C₂₇	108.42	120.00
C₂₃-C₂₇	1.560	1.52	O₃₀-C₂₇-H₂₈	105.66	109.46
C₂₄-H₂₅	1.092	1.11	O₃₀-C₂₇-H₂₉	110.57	109.44
C₂₄-H₂₆	1.097	1.11	H₂₉-C₂₇-C₂₃	107.60	109.46
C₂₄-O₃₂	1.417	1.4	H₂₈-C₂₇-C₂₃	109.91	109.44
C₂₇-H₂₈	1.092	1.11	C₂₇-C₂₃-C₂₄	103.92	109.50
C₂₇-H₂₉	1.097	1.11	C₂₃-C₂₄-H₂₅	109.91	109.46
C₂₇-O₃₀	1.417	1.40	C₂₃-C₂₄-H₂₆	107.61	109.44
O₃₀-H₃₁	0.964	0.94	H₂₆-C₂₄-H₂₅	107.22	109.52
O₃₂-H₃₃	0.964	0.94	H₂₅-C₂₄-O₃₂	105.66	109.46
			H₂₆-C₂₄-O₃₂	110.56	109.44
			C₂₄-0₃₂-H₃₃	108.42	120.00
*Ref [33]

The geometrical parameters of both calculated and experimental values [33] were compared and it exposed in Table 1. The calculated bond lengths are slightly longer than experimental value. This is because the theoretical calculation is done in the gas phase and the experimental work is done in the solid phase [34, 35]. However, as seen in Table 1, there is good agreement between the calculated and the experimental data.

The mean bond lengths of C-C and C-H in the phenyl groups of the molecule were calculated as 1.397 Å and 1.084 Å respectively. From the previous studies, it was determined that the calculated lengths of C-C and C-H bonds in the phenyl groups of the molecule agreed with experimental.

In addition, PES scan analysis was performed around the dihedral angle between C₃-C₂₃-C₁₇-C₁₆ atoms to explain the conformational properties of the 2,2-Diphenyl-1,3-Propanediol. The dihedral angle values for scanning were realized from 0 to 360 degrees in 10-degree increments. It can be clearly visualized in Fig. 2, that a maximum of around 0 degrees was observed with − 731,8501 Hartree around the selected torsion axis during the scan.

Likewise, there is a local minimum corresponding to -731.8596 Hartree at 220º. When the optimization parameters are examined, the dihedral angle between C₃-C₂₃-C₁₇-C₁₆ bonds is 220º. Therefore, it is obvious that the phenyl groups are the most appropriate conformation in the molecule when the structural data and the potential energy surface scanning outcomes are compared.

Vibrational spectral analysis

The main goal of theoretical vibration frequency analysis is to identify the active vibration modes via computed parameters associated with the structure where the molecule is most stable. Theoretical studies are calculated in the gas phase, so there is an incompatibility through experimental studies with solid samples. To resolve this mismatch, the calculated frequencies are scaled by a coefficient called the scaling factor. This scaling factor is different for each basis set [36].

The absence of any imaginary components between the modes in the vibration frequency analysis shows that the optimization process performed in the previous step was true minima. Theoretically calculated vibrational frequencies are scaled through a scaling factor of 0.967 to eliminate the mismatch [37]. The molecule has a non-planar structure with 33 atoms. After scaling, the theoretically calculated vibration frequencies were compared with the experimentally recorded frequencies [16] and it is presented in Table 2. Also, the spectra of vibrational frequencies are given in Fig. 3. Additionally, interpretation of vibration frequency assignment is provided in Table 2 with the aid of the PED% analysis software VEDA 4 and the molecular visualization programme GaussView5.0.8 [38]. The CC, CO, OH, and CH peaks observed between 4000 and 1000 cm^− 1, which is called the functional region in the IR spectrum and it were investigated.

Table 2

Observed and calculated vibrational frequency of 22D13P molecule at B3LYP with 6-311 + + G (d,p) basis set.
Modes	DFT/B3LYP/6-311 + + G(d.p)			Experimental	Assignment
Modes	Unscaled	Scaled	Intensity	Experimental	Assignment
23	633.95	613.03	36.73	622	δCCH %68 + νCC %12
24	634.89	613.93	21.78	632	δCCH %76
25	654.47	632.88	9.85	641	νCC %16 + τCCCH %24
26	710.64	687.19	16.53		δCCH %30 + νCC %14
27	717.89	694.2	0.08		τCCCH %82
28	719.54	695.79	157.85	696	τCCCH %61
29	778.56	752.87	2.38	720	τCCCH %65
30	784.36	758.47	7.81	762	τCCCH %62
31	797.23	770.92	0.01	772	νCC %41
44	1039.54	1005.23	4.6	990	δCCH %39
45	1044.92	1010.44	20.48	995	νCC %34
46	1064.99	1029.84	183.91	1005	νCC %60
47	1072.83	1037.43	21.65	1027	δCCH %13 + νCC %36
48	1075.47	1039.98	303.19	1039	δCCH %10 + νCO %44
49	1099.68	1063.39	0.2	1045	δCCH %13 + νCO %48
50	1114.61	1077.82	174.08	1070	δCCH %51
51	1118.02	1081.13	1.53	1090	δCCH %51
52	1180.9	1141.93	0.89	1129	δCCH %24
53	1183.38	1144.33	0.31		δCCH %42 + νCC %17
59	1289.03	1246.49	0.09		δCCH %14 + νCC %44
60	1323.23	1279.56	2.41		νCC %15
61	1324.53	1280.82	0.13		νCC %62
62	1359.59	1314.72	2		δCCH %51
63	1362.98	1318	18.34		δCCH %58
64	1385.85	1340.11	48.9	1371	δCCH %67
65	1387.28	1341.5	70.81	1379	δCCH %13 + δHCO %51
66	1415.96	1369.23	154.41		δCCH %66
67	1429.01	1381.85	356.79		δCCH %29 + δHCO %12
68	1472.53	1423.94	1.78		δCCH %62
69	1476	1427.29	167.56	1425	δCCH %67
70	1505.24	1455.56	0.39	1430	δHCH %72
71	1518.64	1468.53	3.3	1446	δCCH %24
72	1526.55	1476.17	17.83	1471	δCCH %40 + νCC %25
73	1528.6	1478.15	154.01	1482	δCCH %36 + νCC %24
74	1615.55	1562.23	1.02		νCC %69
75	1618.97	1565.54	193.9		νCC %73
76	1638.64	1584.56	122.77		δCCH %31 + νCC %29
77	1641.28	1587.11	189.95		δCCH %34
78	3004.2	2905.06	206.95	2890	νCH %100
79	3008.6	2909.31	987.37	2901	νCH %95
80	3078.08	2976.51	1433.21	2934	νCH %95
81	3084.21	2982.43	31.76	2958	νCH %100
82	3160.65	3056.35	0.5	3023	νCH %92
83	3160.79	3056.49	64.52	3034	νCH %90
84	3168.95	3064.38	23.39	3055	νCH %87
85	3169.08	3064.5	0.19	3067	νCH %83
86	3179.71	3074.78	17.89	3087	νCH %82
87	3179.83	3074.9	61.3		νCH %85
88	3188.06	3082.86	218.56		νCH %93
89	3188.21	3083	42.42		νCH %90
90	3204.97	3099.21	0.94		νCH %78
91	3205.37	3099.6	7.65	3276	νCH %79
92	3801	3675.40	0	3286	νOH %96
93	3801.47	3676.02	22.16	3307	νOH %96

C-O groups strongly produce stretching vibration bands in the region of 1260 − 1000 cm^− 1 [39–41]. In their study, Krishnakumar et al. observed that, the C-O stretching vibration as 1292 cm^− 1 in the IR spectrum. In this study, C-O vibrations were assigned to 1040 and 1064 cm^− 1 bands in the IR. On the other hand, C-O stretching vibrations of 1,3 propanediol have been experimentally reported in the range of 1040 and 1064 cm^− 1 bands in the literature [16].

According to reports, the C-H groups in aromatic rings exhibit modest stretching vibrations in the IR spectrum between 3100 and 3000 cm^− 1 [42–44]. In the previous study of 1,3-Propanediol as a part of the 22D13P molecule, the aromatic C-H vibrational mode was observed between 3276 to 3023 cm^− 1 [16]. In this study, aromatic C-H vibration bands were intended between 3100 and 3056 cm^− 1. PED analysis showed to facilitate almost 95% of these calculated vibrations came from aromatic C-H vibrations. On the other hand, aliphatic C-H vibrational bands are observed as stretching vibrations in the region of the spectrum between 3000 − 2850 cm^− 1 [45].The aliphatic C-H stretching vibration modes observed in the 2958 and 2890 cm^− 1 [16] bands were assigned to the range of 2982 − 2905 cm^− 1. As was seen in Table 2, the PED analysis revealed that aliphatic C-H stretching vibrations were responsible for about 98% of the contributions in this range.

O-H symmetric stretching vibrations, another group observed in the FT-IR spectrum of the 22D13P molecule; generally, occur in the range of 3600 to 3400 cm^− 1 [46]. The O-H symmetric stretching vibrations were theoretically calculated as 3676 and 3675 cm^− 1respectively. On the other hand, stretching vibration bands of the hydroxyl group were observed in the IR spectrum at 3307 cm^− 1 and 3286 cm^− 1 [16].

The presence of C-C stretching arises between 1650 and 1100cm^− 1 [47]. In the PED analysis of the 22D13P molecule’s vibration bands, the C-C stresses with the highest contributions were 1279.56, 1280.82, 1562.23 and 1565.54 cm^− 1, it was calculated as 15, 62, 69, and 73%, respectively.

Due to the intricacy and presence of vibration bands, it is typically challenging to mark all bands. Therefore, only characteristic bands such as C-O, C-H, O-H, and C-C were examined in this study. As a result, it has been seen that the theoretical results for C-O, C-H, O-H, and C-C vibrations obtained theoretically are compatible with both experimental and literature results.

Molecular orbital investigations

Molecular Orbital theory (MO) is one of the most important quantum mechanical theory describing interactions within molecules. The HOMO represents the highest energy filled molecular orbitals while LUMO represents the lowest energy empty molecular orbitals, respectively. The HOMO-LUMO orbitals of molecules are directly involved in the chemical reactions that take place within the molecule and between the molecule and other molecules [48].

HOMO orbitals behave as electron donors (nucleophilic) in chemical processes, whereas LUMO orbitals behave as electron acceptors (electrophilic). Molecular orbital theory explains the electronic structure and reactivity of molecules quite successfully using these orbitals. By utilizing the HOMO-LUMO orbitals and the energy difference between them, the electronic properties of molecules such as chemical softness (S), chemical hardness (η), ionization potential (I), electron affinity (A), spherical electrophilicity (ω) and spherical electronegativity (χ) can be illuminated [49, 50].

In this study, the HOMO-LUMO molecular orbitals of the 22D13P molecule were calculated, and it shown in Fig. 4. The corresponding values of HOMO-LUMO orbitals and related electronic properties are given in Table 3. As seen in Table 3, the energy of the HOMO and LUMO orbital was − 6.82 and − 0.82 eV respectively, and the energy difference between these orbitals was 6.00 eV. As seen in Fig. 4, the LUMO orbital is located on the phenyl rings, while the HOMO orbitals are spread over the whole molecule.

Table 3

The total energy, comparison of HOMO-LUMO energy gaps and related molecular properties of the 22D13P molecule with B3LYP/6-311 + + G(d,p) level.
Descriptors (eV)	22D13P (eV)
HOMO energy ΔE_HOMO	-6.82
LUMO energy ΔE_LUMO	-0.82
Energy gap ΔE_HOMO−LUMO (E_g)	6.00
Ionization potential (I)	0.82
Electron affinity (A)	6.82
Electro negativity (χ)	3.82
Global hardness (η)	3.00
Chemical softness (S)	-0.16
Chemical potential (µ)	-3.82
Electrophilicity index (ɷ)	-21.89

The HOMO-LUMO energy difference (ΔE) values greater than 1.5 eV mean that the molecules are thermodynamically stable and resistant. Thermodynamic stability occurs when a system is at its lowest energy level or is in chemical equilibrium with its environment. Therefore, the energy difference of 6eV showed that the compound was thermodynamically stable. The electronic transition of the molecule was determined using HOMO-LUMO molecular orbital analysis, and the UV-vis spectrum analysis was carried out in the gas phase with the aid of the Gaussian 09w package programme. Table 4 lists the computed UV spectroscopic parameters. It shows that, in which levels the transitions occur between major contribution rates of HOMO-LUMO orbitals occur together with their percentage contributions. As shown in Table 4, the theoretical absorption values at 235, 234, and 232 nm are related to the oscillator frequencies of 0.0164, 0.0262, and 0.0598, and their major contributions are HOMO→LUMO + 1 (28%), HOMO→LUMO (23%), HOMO→LUMO (58%), respectively.

Table 4

Experimental and theoretical electronic absorption spectra values such as, absorption wavelength λ(nm),excitation energies E(eV) and oscillator strengths (f) of the 22D13P molecule using TD-DFT method via B3LYP/6-311G++(d,p) basis set.
TD-B3LYP/6-311G++(d,p)			Transitions
$?\left(\mathbf{n}\mathbf{m}\right)$	$\mathbf{E}\left(\mathbf{e}\mathbf{V}\right)$	$\left(\varvec{f}\right)$	Major Contribution
235	5.28	0.0164	H-3→LUMO (26%), H-2→L + 1 (22%), HOMO→L + 1 (28%)
234	5.30	0.0262	HOMO→LUMO (23%), HOMO→L + 2 (22%), H-1→L + 3 (14%)
232	5.34	0.0598	HOMO→LUMO (58%), HOMO→L + 2 (11%)

NMR spectral analysis

NMR is a useful method for interpreting and predicting the structure of organic molecules. In this study, ¹H and ¹³C-NMR studies were carried out with the help of quantum chemical computation techniques by interpreting the structure of the 22D13P compound and comparing it with the experimental results. The ¹H and ¹³C NMR spectra of the 22D13P molecule were calculated with the B3LYP level and the 6-311G++(d,p) basis set using the atomic orbital (GIAO) method including Gauge on fully optimized geometry. On the other hand, the chemical shift values of the 22D13P molecule were experimentally recorded in CDCl3 (Deuterated Chloroform) solvent [16]. The observed and theoretically calculated chemical shift values for ¹H and ¹³C NMR are given in Table 5. The correlation R² values among the computed and experimental values of ¹H NMR and ¹³C-NMR for the 22D13P molecule were found to be 0.9758 and 0.9941 respectively.

Table 5

Experimental and calculated ¹H and ¹³C isotropic chemical shifts (based on TMS) of the 22D13P molecule
C Atoms	B3LYP	Exp.	H Atoms	B3LYP	Exp.
C₁	133.63	128.20	H₇	7.78	7.29
C₂	134.11	128.47	H₈	7.95	7.17
C₃	150.88	143.18	H₉	7.06	7.17
C₄	135.38	128.47	H₁₀	7.51	7.29
C₅	132.92	128.20	H₁₁	7.52	7.21
C₆	131.16	126.76	H₁₈	7.06	7.17
C₁₂	135.38	128.47	H₁₉	7.51	7.29
C₁₃	132.93	128.20	H₂₀	7.52	7.21
C₁₄	131.16	126.76	H₂₁	7.78	7.29
C₁₅	133.63	128.20	H₂₂	7.95	7.17
C₁₆	134.12	128.47	H₂₅	4.26	4.28
C₁₇	150.88	143.18	H₂₆	3.27	4.28
C₂₃	62.73	53.18	H₂₈	4.26	4.28
C₂₄	69.35	68.33	H₂₉	3.27	4.28
C₂₇	69.35	68.33	H₃₁	0.78	2.50
			H₃₃	0.78	2.50

Natural Bonding Orbital Analysis (NBO)

Natural bond orbital analysis (NBO) examines all possible interactions between "full" (donor) Lewis’s type NBOs and "empty" (acceptor) non-Lewis NBOs. The energetic significance of these interactions is determined by predicting the 2nd order perturbation theory [51–53]. In this study, NBO analysis was performed on the optimized structure of the 22D13P molecule to obtain a quantitative view of electron transfer within the molecule.

$$E\left(2\right)=?{E}_{ij}={q}_{i}\frac{{F\left(i,j\right)}^{2}}{{e}_{i}-{e}_{j}}$$

Where; 𝐹𝑖𝑗² is the Fock matrix element between the i and j NBO orbitals, ε_j and ε_i are the acceptor and donor NBO orbitals, and qi is the occupancy rate of the donor orbital. Electron transfer from the NBO donor NBO(i) to the NBO acceptor NBO(j) determines the stability of the system. In this study, NBO analysis was done theoretically. Some selected NBO data with stabilization energy value (E2) of the 22D13P molecule > 10 kcal/mol are presented in Table 6. From the Table 6, it can be clearly understood that the bonding π electrons are transferred to the π* antibonding orbitals of the π orbitals through both benzene rings of the 22D13P compound. The total stabilization energies for both benzene rings were found to be equal at 122.54 kcal/mol.

Table 6

Second-order perturbation theory analysis of Fock matrix in NBO basis corresponding to the most important transfer interactions (donor-receiver) of the 22D13P molecule
Donor NBO (i)	Acceptor NBO (j)	E(2) kcal/mol	E(j)-E(i) a.u.	F(i.j) a.u.
π (C 1 - C 6)	π* (C 4 - C 5)	21.26	0.28	0.069
π (C 14 - C 15)	π* (C 12 - C 13)	21.26	0.28	0.069
π (C 2 - C 3)	π* (C 1 - C 6)	20.75	0.28	0.068
π (C 16 - C 17)	π* (C 14 - C 15)	20.75	0.28	0.068
π (C 4 - C 5)	π* (C 2 - C 3)	20.57	0.29	0.069
π (C 12 - C 13)	π* (C 16 - C 17)	20.57	0.29	0.069
π (C 2 - C 3)	π* (C 4 - C 5)	20.28	0.28	0.067
π (C 16 - C 17)	π* (C 12 - C 13)	20.28	0.28	0.067
π (C 1 - C 6)	π* (C 2 - C 3)	20.09	0.29	0.068
π (C 14 - C 15)	π* (C 16 - C 17)	20.09	0.29	0.068
π (C 4 - C 5)	π* (C 1 - C 6)	19.59	0.29	0.067
π (C 12 - C 13)	π* (C 14 - C 15)	19.59	0.29	0.067

Drug-likeness Analysis

The Lipinski analysis determines if the 22D13P molecule has a drug-like structure. The Lipinski's rule of five is an analysis method used to calculate the drug similarity of a compound, as well as to determine whether a chemical compound with a certain pharmacological or biological activity and it can be used as an orally active drug in humans [54]. The basis of the Lipinski analysis is based on the satisfaction of five criteria. These criteria should be ≤ 5 for Hydrogen bond acceptor (HBA), ≤ 10 for Hydrogen bond donor (HBD), ≤ 500 for molecular weight (MW) and ≤ 5 for LogP of the compound. HBA, HBD, Molecular mass (MW) and octanol-water partition coefficients (LogP) values of the 22D13P compound were 2, 2, 228.2 and 2.3 respectively. It confirms that, the compound does not violate the Lipinski criteria; it indicates that the compound can be allowed for oral absorption.

In this study, Swiss-ADME, a widely used free web tool for the analysis of physico-chemical properties and pharmacokinetics of known drugs or new drug candidate molecules, was used to analyze the compliance of the 22D13P molecule with Lipinski criteria. The values of the related criteria calculated as a result of the analysis of the 22D13P molecule with Swiss-ADME and the comparison of these values with the Lipinski criteria are given in Table 7. As seen in Table 7 none of the relevant criteria for the 22D13P compound violated the Lipinski criteria. Calculated results show that the 22D13P compound complies with Lipinski rules. This means that there is no violation in the use of the 22D13P molecule as a drug.

Table 7

Drug likeness parameters of 2,2-Diphenyl-1,3-Propandiol molecule.
Conformers	Final Intermolecular Energy (1)	Final Total Internal Energy (2)	Torsional Free Energy (3)	Unbound System's Energy (4)	Binging free energy [=(1)+(2)+(3)-(4)]
1	-8.80	-1.77	1.79	-1.77	-7.01
2	-8.55	-1.90	1.79	-1.90	-6.76
3	-8.54	-1.85	1.79	-1.85	-6.75
4	-8.52	-1.90	1.79	-1.90	-6.73
5	-8.50	-1.90	1.79	-1.90	-6.71
6	-8.49	-1.85	1.79	-1.85	-6.70
7	-8.44	-1.84	1.79	-1.84	-6.65
8	-8.37	-1.74	1.79	-1.74	-6.59
9	-8.30	-1.88	1.79	-1.88	-6.51
10	-8.15	-1.85	1.79	-1.85	-6.36

On the other hand, the number of rotatable bonds of the 22D13P molecule has been calculated as 4, which means that this molecule is flexible because the value is below 10. The number of rotatable bonds is a topological parameter that assesses the molecular elasticity of a drug. Another important criterion for a drug molecule is the topological polar surface area. The topological polar surface area is a very useful measure for predicting the drug transport properties of compounds. The TPSA value is expected to be below 140 Å. In the calculation made, the TSPA value of the 22D13P molecule was found to be 40.46 Å.

Molecular Docking Study

In a virtual scan with the swiss target prediction tools confirms that, the ER (Estrogen receptor) family has given highest scores with the 2,2-Diphenyl-1,3-Propanediol. Therefore, the (6I65) protein from the Estrogen related receptor (ER receptor) family was chosen for the molecular docking study. The molecule exactly binds in the active site of the protein and it forms intermolecular interactions with Leu268, Cys269, Ala272, Glu275, Met306, Ile310, Val313 and Tyr326. The 10 conformations produced by Auto dock in the molecular docking study are given in Table 8. From Table 8, the binding affinity for the best binding pose between the ERRγ and 22D13P compound was calculated as -7.01 kcal/mol. The intermolecular interactions of the best pose obtained in the molecular docking study are presented in Table 9. The molecule forms Pi-Alkyl and carbon H-bond interactions with Leu268 (5.34, 2.77 Å) and Ala272 (3.72, 2.10 Å). And also, the molecule forms Pi-Sulfur interactions with Cys269 (4.85 Å) and Met306 (5.09 Å) respectively. In addition, the molecule forms Pi-Pi T-shaped interactions with Tyr326 (4.60 Å). Notably, the molecule forms two conventional H-bond with Glu275 at the distance of 1.87 and 2.28 Å respectively. These are the important interactions and it stabilizes the molecule with the active site of Estrogen-related receptor gamma (ERRγ). The 3D (a) and 2D (b) visualizations of the interactions between the Diphenyl-1,3-Propanediol and ERRγreceptor are shown in Fig. 5.

Table 8

Binding free energy values of 22D13P molecule with human estrogen-related receptor gamma (ERRγ)
Descriptors	Accepted range	Calculated
Molecular mass (Da) (MW)	≤ 500	228.29
Hydrogen band donor (HBD)	≤ 5	2
Hydrogen band acceptor (HBA)	≤ 10	2
LogP	≤ 5	2.34

Table 9

Intermolecular interactions of 22D13P molecule with human estrogen-related receptor gamma (ERRγ) enzyme
Active site residues	Ligand∙∙∙amino acid residue and atom identifier	Distance (Å)
Active site residues	Ligand∙∙∙amino acid residue and atom identifier	Docking	MD simulation
Leu268	Pi-Alkyl interactions Benzene ring∙∙∙CG/Leu268 Carbon H-bond H∙∙∙O/Leu268	5.34 2.77	* *
Cys269	Pi-Sulfur interactions Benzene ring∙∙∙ SG/Cys269	4.85	***
Ala272	Pi-Alkyl interactions Benzene ring∙∙∙CB/Ala272 Carbon H-bond H∙∙∙O/Ala272	3.72 2.10	3.44 * *
Glu275	Conventional H-bond H∙∙∙O/Glu275 H∙∙∙O/Glu275	1.87 2.28	* *
Met306	Pi-Sulfur interactions Benzene ring∙∙∙SG/Met306	5.09	5.71
Ile310	Pi-Alkyl interactions Benzene ring∙∙∙C/Ile310 Carbon H-bond O∙∙∙H/Ile310	4.57 ***	*** 2.91
Val313	Pi-Alkyl interactions Benzene ring∙∙∙CG/Val313	4.48	***
Tyr326	Pi-Pi T-shaped interactions Benzene ring∙∙∙Benzene ring/Tyr326	4.60	***
Leu345	Pi-Alkyl interactions Benzene ring∙∙∙CG/Leu345	***	5.15
Ala431	Pi-Alkyl interactions Benzene ring∙∙∙CB/Ala431	***	5.21
Phe435	Pi-Pi T-shaped interactions Benzene ring∙∙∙Benzene ring/Phe435 Benzene ring∙∙∙Benzene ring/Phe435	* *	5.02 3.82
*** - Represents no interactions

Molecular dynamics simulation

The molecular dynamics simulation was performed to find out the stability and conformational modifications of ligand and protein molecules. The best pose selected from the molecular docking study and it was subjected into molecular dynamics simulation. Table 9 shows the intermolecular interactions between 2,2-diphenyl-1,3-propanedioland human estrogen-related receptor gamma (ERRγ) during the MD simulation. Notably, the Pi-Alkyl and Pi-Sulfur interactions of the molecule with ERRγ are retained in the MD simulation. The molecule form Pi-Alkyl interactions with Ala272 at the distance of 3.72 Å; it is retained during the MD simulation (3.44 Å). Similarly, the molecule forms Pi-Sulfur interactions with Met306 (5.09 Å) and it is retained during the MD simulation (5.71 Å). In addition to that, the molecule forms Pi-Alkyl and Pi-Pi T-Shaped interactions with Leu345, Ala431 and Phe435 at the distance of 5.15, 5.21, 5.02 and 3.82 Å respectively. Figure 6 (a,b) shows the intermolecular interactions of 22D13P molecule with ERRγ during the MD simulation.

Further, the RMSD, RMSF, Rg and total no of hydrogen bond of 22D13P - ERRγ complex were calculated from the MD analysis [Figure 7 (a-d)]. The RMSD analysis confirms that, the molecule get stabilized after 10 ns. The values are lies in between 1.25–1.8 Å and the variation is ~ 0.55 Å (Fig. 7a). The RMSF shows that the fluctuation of individual amino acids during the MD simulation (Fig. 7b). The amino acid Tyr234 (18.6 Å) and Gly405 (18.4 Å) exhibits high fluctuation compared with other residues. On the other hand, Ala272 (10.4 Å), Met306 (9.7 Å), Leu345 (10.9 Å), Ala431 (9.8 Å) and Phe435 (10.0 Å) gives the lowest RMSF values; because the 22D13P molecule forms strong hydrophobic interactions with those residues during the MD simulation. The compactness of the protein molecule is determined from the Radius of Gyration (Rg) analysis. The Rg values are lies between 17.7 to 18.1 Å; indicates that the binding of 22D13P molecule is not much affected the compactness of the protein (Fig. 7c). The total number hydrogen bonds of 22D13P - ERR gamma complex is ~ 110; it stabilizes the structure of the protein during the MD simulation.

The most stable structure of the 22D13P molecule was calculated using the DFT/B3LYP level and the 6-311 + + G(d,p) basis set. The calculated optimized structure parameters are quite consistent when compared with similar structures in the literature. When comparing the experimentally recorded and theoretically computed ¹H-NMR and ¹³C-NMR values, both the carbon and hydrogen chemical shifts are in good agreement with each other. NBO analysis clearly shows that intermolecular charge transfer occurs via benzene rings. When Lipinski's five criteria were applied to the drug likeness values, they confirmed that no violations had occurred. So, 22D13P has positive pharmacological properties. The intermolecular interactions between 22D13P and ERR gamma were analyzed using molecular docking study; it conforms that, the molecule bind in the active site and it forms key interactions. Finally, the MD simulation conforms that the molecule is stable in the active site of ERR gamma. It reveals that the molecule has the potential to inhibit the estrogen receptor, which triggers the development of breast cancer.

Acknowledgement

This study has been supported by Pamukkale University (Grant No: 2013FBE013). The authors thank to "Bioinformatics Resources and Applications Facility (BRAF), C-DAC, Pune, for providing the supercomputing facility.

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Competing Interest

There are no conflicts of interest to declare for each contributing author.

Authors’ contribution

Alpaslan Bayrakdar - Software, Conceptualization, Formal analysis, Investigation, Data Curation,

Methodology, Validation, Writing - Original Draft, Writing - Review & amp; Editing.

Sivanandam Magudeeswaran- Software, Validation, Investigation, Writing.

Prasath Manivannan- Supervision, Correction.

Sathya Bangaru - Software, Validation, Investigation, Writing.

Funding - The authors did not receive funds, grants, or other support from any organization for the submitted work.

Availability of data and materials

Not applicable.

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Spectroscopic and an active site analysis of 2,2-diphenyl-1,3- propanediol as antitumor and inflammatory potential

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Abstract

Figures

Introduction

Experimental and theoretical procedures

Quantum chemical and spectroscopic calculations

Molecular docking analysis

Molecular dynamics simulation

Results and discussion

Molecular structure features

Vibrational spectral analysis

Molecular orbital investigations

NMR spectral analysis

Natural Bonding Orbital Analysis (NBO)

Drug-likeness Analysis

Molecular Docking Study

Molecular dynamics simulation

Conclusion

Declarations

References

Additional Declarations

Status:

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TD-B3LYP/6-311G++(d,p)			Transitions
\(?\left(\mathbf{n}\mathbf{m}\right)\)	\(\mathbf{E}\left(\mathbf{e}\mathbf{V}\right)\)	\(\left(\varvec{f}\right)\)	Major Contribution
235	5.28	0.0164	H-3→LUMO (26%), H-2→L + 1 (22%), HOMO→L + 1 (28%)
234	5.30	0.0262	HOMO→LUMO (23%), HOMO→L + 2 (22%), H-1→L + 3 (14%)
232	5.34	0.0598	HOMO→LUMO (58%), HOMO→L + 2 (11%)