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Investigations of structural, spectral and electronic properties of enrofloxacin and boron complexes via quantum chemical calculation and molecular docking
Spectrochimica Acta Part A: Molecular and Biomolecular Spectroscopy 220 (2019) 117102
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Spectrochimica Acta Part A: Molecular and Biomolecular Spectroscopy journal homepage: www.elsevier.com/locate/saa
Investigations of structural, spectral and electronic properties of enrofloxacin and boron complexes via quantum chemical calculation and molecular docking Koray Sayin ⁎, Ayhan Üngördü Department of Chemistry, Faculty of Science, Sivas Cumhuriyet University, 58140 Sivas, Turkey
a r t i c l e
i n f o
Article history: Received 13 September 2018 Received in revised form 24 April 2019 Accepted 9 May 2019 Available online 11 May 2019 Keywords: Modelling studies Biological activity Molecular docking ADME NLO properties
a b s t r a c t Quantum chemical analyses were performed over enrofloxacin and boron complexes. The most stable isomer of enrofloxacin was examined at M062X/6-31+G(d) level in gas phase. Structural and spectral characterizations of enrofloxacin and its complexes were performed at same level of theory. MEP maps of studied compound were calculated via ESP charges analyses. Some quantum chemical descriptors (QCDs) were calculated to determine the non-linear optical (NLO) and biological reactivity of studied molecules. Furthermore, molecular docking calculations between boron complexes and a protein (ID: 2ITN and 2ITV) were done. ADME analyses were done in the determination of the best drug candidate. As a result, complex (3) was found as the best in the NLO applications and it was found that complex (1) and (3) have similar biological reactivity in lung cancer treatment. © 2019 Elsevier B.V. All rights reserved.
1. Introduction Fluoroquinolone is the member of quinolone family and this group is known as antibiotics. The antibiotics show their effect by preventing the deoxyribonucleic acid in the target cell. Antibiotics have both beneficial and detrimental effect to environment or livings [1–9]. Chemicals with boron atom have broad applications in many fields. Especially, these compounds attract the attention with their applications in optics and medicine. In recent years, importance of boron mineral in medicine is increasing. In the treatment, patient cells are selected and destroyed, and healthy cells are damaged to a minimum level. In this study, 1cyclopropyl-7-(4-ethylpiperazin-1-yl)-6-fluoro-4-oxo-1,4dihydroquinoline-3-carboxylic acid (enrofloxacin) and its boron complexes are investigated via quantum chemical calculations. Investigations over some boron complexes with enrofloxacin which are represented in Scheme 1 are performed. Complex (1) has been synthesized by Wang et al. and there is not structural data in their paper [10]. Quantum chemical calculations of similar boron complexes have been published by Sayin and coworkers [11,12]. Enrofloxacin and its boron complexes are investigated in detail in this paper. M06-2X/6-31+G(d) level has been found as the ⁎ Corresponding author. E-mail address: [email protected] (K. Sayin). E-mail address: [email protected] (K. Sayin).
https://doi.org/10.1016/j.saa.2019.05.007 1386-1425/© 2019 Elsevier B.V. All rights reserved.
best calculation level for this type compounds [11,12]. Therefore, same level of theory is used in this study. Firstly, enrofloxacin is examined in detail. Conformational analyses of enrofloxacin are performed in this paper. The most stable isomer for enrofloxacin is determined by using thermodynamic parameters, total energy (ETotal), enthalpy (H), and Gibbs free energy (G). Structural and spectral (IR and NMR) analyses of the most stable isomer are performed. Enrofloxacin is deprotonated and re-optimized at same level of theory. Then molecular electrostatic potential (MEP) map of it is calculated via electro-static potential (ESP) charges to determine the electro-rich regions to coordinate with boron. The last part of this paper is the boron complexes. Mentioned complexes are optimized at same level of theory in gas phase and water. IR spectrum of studied boron complexes are calculated and examined by using VEDA 4XX program. Chemical shift values of carbon and hydrogen atoms are calculated against tetramethylsilane. MEP maps of related boron complexes are investigated in gas phase and water. Some quantum chemical descriptors (QCDs) are calculated in gas phase to investigate non-linear optical (NLO) properties. Finally, some QCDs are re-calculated in water to investigate the biological properties. Enrofloxacin and its boron complexes are interacted with 2ITN and 2ITV target cell by molecular docking calculations. So, the best drug candidate for lung cancer is determined by using interaction energies. Additionally, Absorption, distribution, metabolism and excretion (ADME) analyses are performed for studied complexes. The best drug respect to physicochemical, lipophilicity, water solubility,
2
K. Sayin, A. Üngördü / Spectrochimica Acta Part A: Molecular and Biomolecular Spectroscopy 220 (2019) 117102 Table 1 Mentioned thermodynamic parameters of each isomer. Isomers 1 2 3 4 5 6 a
Scheme 1. Schematic diagram of investigated boron complexes with atomic labelling. R: -F− (1), -Cl− (2), and -Br− (3).
ETotala
Ha
Ga
−769,413.72 −769,414.06 −769,413.24 −769,421.44 −769,421.79 −769,420.98
−769,413.13 −769,413.47 −769,412.65 −769,420.85 −769,421.20 −769,420.39
−769,461.03 −769,461.33 −769,461.09 −769,468.03 −769,468.50 −769,467.98
In kcal/mol.
the lowest unoccupied molecular orbital (ELUMO), ionization energy (I), electron affinity (A), energy gap (EGAP), absolute hardness (η), absolute softness (σ), optical softness (σO), global softness (S), absolute electronegativity (χ), chemical potential (CP), electrophilicity index (ω), nucleophilicity index (N), additional electronic charges (ΔNMax) and polarizability (α) were used as QCDs. EHOMO, ELUMO and α were directly taken from calculation results. The other descriptors were calculated by using Eqs. (1)–(9) [18–20]. I ¼ −EHOMO
ð1Þ
pharmacokinetics, druglikeness and medicinal chemistry properties are determined in detail.
A ¼ −ELUMO
ð2Þ
2. Calculation method
EGAP ¼ ELUMO −EHOMO
ð3Þ
Molecular simulation calculations were performed by Gaussian package program [12–15]. Input file of enrofloxacin and the boron complexes were prepared by using ChemDraw Professional 15.1 and GausView 5.0.8 programs [16]. Pre-calculations and full-calculations were performed by using Gaussian IA32W-G09RevA.02 and Gaussian AS64L-G09RevD.01 programs, respectively. Investigated compounds were re-optimized by using M06-2X method, one of the hybrid density functional theory (DFT) functions, with 6-31+G(d) basis set in gas phase and water. For calculation in water, conductor like polarized continuum model (C-PCM) was taken into consideration in solute – solvent interactions. Some conformational structures of enrofloxacin were drawn and optimized at same level of theory. The most stable conformer was determined by thermodynamic parameters. MEP map and contour of it were calculated and examined in detail. Boron was coordinated to it from electrophilic regions. VEDA 4XX program was used in the determination of vibration modes in studied complexes [17]. Additionally, tetramethylsilane was used as a reference substance for carbon and hydrogen atoms. Some quantum chemical descriptors which are energy of the highest occupied molecular orbital (EHOMO), energy of
η¼
I−A ELUMO −EHOMO ¼ 2 2
ð4Þ
σ¼
1 η
ð5Þ
σO ¼
χ¼
1 EGAP
jI þ Aj j−EHOMO −ELUMO j ¼ 2 2
ð6Þ
ð7Þ
CP ¼ −χ
ð8Þ
CP ΔNMax ¼ − η
ð9Þ
CP2 2η
ð10Þ
ω¼
Scheme 2. Schematic diagram of conformer of ciprofloxacin.
K. Sayin, A. Üngördü / Spectrochimica Acta Part A: Molecular and Biomolecular Spectroscopy 220 (2019) 117102
3
Fig. 1. Optimized structure of enrofloxacin.
Fig. 2. Calculated IR spectrum for enrofloxacin.
1 N¼ ω S¼
1 2η
ð11Þ
ð12Þ
In addition to them, Chemissian Version 4.43 was used in taking images of MOED [21]. Chemcraft Version 1.8 was used in interpreting of NMR spectrums [22]. Molecular docking calculations are done by using Hex program (Version:8.0.0) [23]. Finally, ADME analysis were done by using SwissADME web tool [24]. 3. Result and discussion 3.1. Analyses of enrofloxacin Schematic diagram of enrofloxacin and isomers are shown in Scheme 2. The most stable isomer is determined by using thermodynamic parameters which are total energy (ETotal), enthalpy (H) and Gibbs free energy (G). All calculations are performed at M06-2X/6-31 +(d) level in gas phase and obtained results are given in Table 1.
Table 2 Calculated NMR results of mentioned molecule at M062X/6-31+G(d) level. 13
1
C NMR results
C2 C4 C5 C6 C8 C9 C10 C11 C12 C13 C17 C18 C20 C21 C22 C23 C24 C25 C26
169.2 186.6 123.5 159.5 147.8 135.1 126.9 157.6 154.2 116.8 53.6 51.5 55.4 52.1 36.7 12.0 7.2 55.5 15.0
H NMR results
O1H C6H C10H C13H C17H C17H″ C18H C18H″ C20H C20H′ C21H C21H′ C22H C23H C23H′ C24H C24H′ C26H C26H′ C27H C27H′ C27H″
11.9 9.1 8.4 7.8 4.1 3.3 2.7 1.9 3.0 2.7 3.8 3.6 3.0 1.1 0.8 1.4 1.4 2.5 1.9 1.2 1.1 1.0
4
K. Sayin, A. Üngördü / Spectrochimica Acta Part A: Molecular and Biomolecular Spectroscopy 220 (2019) 117102
Fig. 3. Optimized structure and MEP map of deprotonated enrofloxacin.
Fig. 4. Optimized structures of studied boron complexes with ciprofloxacin in gas phase.
According to Table 1, isomer 5 has the lowest ETotal, H and G. This result show that the most stable structure is isomer 5. This molecule is taken into account for other calculations. Optimized structure and atomic labelling of isomer 5 are represented in Fig. 1. IR spectrum of isomer 5 is calculated to characterize the molecular structure. Calculated IR spectrum and harmonic frequencies of some selected peaks are represented in Fig. 2. The calculated frequencies are harmonic values while frequencies obtained via experimentally techniques are anharmonic values. Due to the fact that, there may be some differences between calculated and experimental frequencies. As experimentally, OH stretching frequencies have been calculated in the range of 3250–3730 cm−1 [25–27]; 1578–1730 cm−1 for C_O stretching frequencies [28–31]; 1400–1575 cm−1 for C_C stretching frequencies [32,33] and 1251–1614 cm−1 for C_N stretching frequencies [33]. According to these data, the calculated frequencies are in the agreement with published frequencies. NMR spectrum of isomer 5 is calculated to calculate the chemical shift values of carbon and hydrogen atoms. Chemical shift values of carbon and hydrogen atoms are given in Table 2. According to Table 1, chemical shift values of aliphatic carbon atoms are calculated in the range of 7–55 ppm; 116–186 ppm for aromatic carbon atoms; 7.8–9.1 ppm for aliphatic hydrogen atoms and 0.8–4.1 ppm for aromatic hydrogen atoms. Enrofloxacin is deprotonated from OH proton in carboxyl group of ciprofloxacin ligand. Optimized structure at the same level of obtained anion is given in Fig. 3. MEP maps are calculated at the same level of theory and represented in Fig. 3.
According to MEP map in Fig. 3., there is red area at environment of oxygen atoms (especially in carboxyl group). Electron density is higher in this region than others. These regions are appropriate for nucleophilic attack. Table 3 Some geometric parameters belong to mentioned molecules at M062X/6-31+G(d) level in vacuo. Assignments
Complex (1)
Complex (2)
Complex (3)
Bond length (Å) B-R1′ B-R2′ B-O1 B-O15 C2-O3 C4-O15 C11-F14 N7-C22
1.381 1.358 1.476 1.551 1.212 1.280 1.345 1.450
1.871 1.818 1.458 1.517 1.209 1.288 1.344 1.451
2.051 1.967 1.451 1.502 1.208 1.292 1.343 1.452
Bond angle (deg.) R1′-B-R2′ R1′-B-O1 R1′-B-O15 R2′-B-O1 R2′-B-O15 O1-B-O15 O1-C2-O3 O1-C2-C5 O15-C4-C5
114.90 110.13 104.99 110.55 106.95 108.99 124.85 114.42 121.99
113.46 109.56 105.25 110.37 107.59 110.48 124.31 114.30 121.84
114.29 108.95 103.75 110.82 108.03 110.80 124.13 114.24 121.74
K. Sayin, A. Üngördü / Spectrochimica Acta Part A: Molecular and Biomolecular Spectroscopy 220 (2019) 117102
5
1 2 8
3 7 4
6
5
(1) 1 2 3 6
4
7
5
(2) 1 2 3 6
4
7
5
(3) Fig. 5. IR spectrum of mentioned complexes at M062X/6-31+G(d) level in gas phase.
3.2. Boron complexes
Table 4 Analysis of IR spectrum. Peak assignments
Frequency (cm−1)
Vibration modesa
In complex (1) 1 2 3 4 5 6 7 8
3112 2968 1855 1716 1566 1280 1116 938
S (aliphatic CH) S (aliphatic CH) S (C=O) S (C=O) S (C=N) and B (H-C-C) S (B-F′) S (B-F′) and S (B\ \O) S (B\ \O), B (C-C-C in ring) and B (O-C-O)
In complex (2) 1 2 3 4 5 6 7
3115 2964 1862 1716 1563 1310 900
S (aliphatic CH) S (aliphatic CH) S (C=O) S (C=O) and S (C=N) S (C=O) and B (H-C-C) S (C\ \F) S (B-Cl′), B (B-O-C) and O (Cl-O-O-B)
In complex (3) 1 2 3 4 5 6 7
3114 2977 1863 1718 1559 1306 900
S (aliphatic CH) S (aliphatic CH) S (C=O) S (C=O) and S (C=N) S (C=O) and B (H-C-C) S (C\ \O) S (B-Br′) and B (B-O-C)
a
Vibration Modes: S: Stretching; B: Bending; O: Out.
3.2.1. Optimization and spectral analyses The boron complexes are optimized at M06-2X/6-31+G(d) level in gas phase and water. Optimized structures are represented in Fig. 4 and some geometric parameters are given in Table 3. The bond lengths between boron and halogens are calculated in the range of 1.35–2.05 Å. As for the published data, these bond lengths have been reported in the range of 1.36–2.0 Å [34]. Additionally, the B\\O bond length is calculated in the range of 1.45–1.55 Å while it has been reported in the range of 1.40–1.60 Å [35,36]. According to these values, the calculated results are in the agreement with published results. Bond angles environment of boron atom are calculated as nearly 1100. This result implies the geometric structure of environment of center atom is distorted tetrahedral in each studied complex. Spectral analyses (IR and NMR) are done for each complex. IR spectrum of the boron complexes are calculated at same level of theory in gas phase and given in Fig. 5. Some peaks are labelled in IR spectrum and they are examined by VEDA 4XX program and given in Table 4. For complex (1), stretching frequencies of “C=O” bond, “C= Opyridine” bond “B-F” and “B-O” have been reported as 1716 (1855)calculated; 1635 (1716)calculated; 1148 (1280)calculated and 1053 (1116)calculated, respectively. There are some differences between experimental and calculated results due to the harmonic and anharmonic properties. Generally, there is a good agreement between experimental and calculated results. Chemical shift values of carbon and hydrogen atoms are calculated to get data about complex structures. Tetramethylsilane and
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Table 5 Chemical shift values of carbon and hydrogen atoms in mentioned complexes. 13
1
C NMR
H NMR
Assignments
Comp. (1)
Comp. (2)
Comp. (3)
Assignments
Comp. (1)
Comp. (2)
Comp. (3)
C2 C4 C5 C6 C8 C9 C10 C11 C12 C13 C17 C18 C20 C21 C22 C23 C24 C25 C26 – –
164.8 185.4 122.9 160.3 147.9 127.3 126.8 159.5 156.6 115.2 54.5 52.3 54.0 51.4 37.2 11.9 8.5 56.6 13.9 – –
162.9 182.8 122.2 159.1 148.4 126.5 127.7 158.5 157.7 115.5 53.9 51.4 54.3 51.8 38.0 11.3 9.0 56.0 14.1 – –
163.1 184.9 124.9 158.5 148.2 146.3 125.1 160.7 157.7 115.2 53.1 51.4 55.3 52.0 37.0 11.3 10.1 54.3 14.8 – –
C6H C10H C13H C17H C17H′ C18H C18H′ C20H C20H′ C21H C21H′ C22H C23H C23H′ C24H C24H′ C25H C25H′ C26H C26H′ C26H″
9.1 8.9 7.9 4.2 3.5 2.9 1.6 2.8 2.4 3.7 3.6 3.2 1.3 0.8 1.5 1.5 2.3 1.8 1.3 1.2 1.1
9.2 8.9 7.9 4.1 3.5 3.0 1.5 2.9 2.6 3.7 3.7 3.4 1.4 0.8 1.6 1.4 2.3 1.9 1.2 1.1 1.1
9.3 9.0 8.0 4.0 3.6 4.0 1.8 3.0 2.8 3.8 3.7 3.4 1.5 0.8 1.7 1.3 2.5 2.0 1.2 1.1 1.0
trichlorofluoromethane is used as reference substance for carbon/hydrogen and fluorine atoms, respectively. NMR spectrum of studied complexes are calculated at M062X/6-31+G(d) level in gas phase. Chemical shift values of carbon and hydrogen atoms are given in Table 5. These results are in agreement with theoretical expectation and published articles. The chemical shift values are calculated in the range of 8.5–56.6 ppm and 115.2–185.4 ppm for aliphatic and aromatic carbon atoms, respectively. Chemical shift values of hydrogen atoms which are coordinated to aliphatic and aromatic carbon atoms are calculated as in the range of 1.0–4.2 ppm and 7.9–9.3 ppm, respectively. 3.2.2. Non-linear optical (NLO) activity NLO activities are important for telecommunication industry. NLO activity increases with the increasing of molecular planarity and π electron delocalization. Furthermore, some QCDs can be used in the determination of NLO properties. QCDs to be examined are energy of the highest occupied molecular orbital (EHOMO), energy of the lowest unoccupied molecular orbital (ELUMO), ionization energy (I), electron affinity (A), energy gap (EGAP), absolute hardness (η), absolute softness (σ), optical softness (σO), absolute electronegativity (χ), additional electronic charges (ΔNMax) and polarizability (α). Mentioned QCDs of enrofloxacin and its boron complexes are calculated in gas phase by using Eqs. (1)–(9) and given in Table 6. The first parameter is the EHOMO. If its energy is high, compounds may give electron more easily. It implies that NLO properties and activities increases with increasing of the energy of HOMO. Second
parameter is the energy of LUMO. If the ELUMO value is low, compounds can accept electrons and this result shows that non-linear optical activity of studied compounds increase with decreasing of ELUMO. Third parameter is energy gap between frontier molecular orbitals. Electron freedom is significant in determination of NLO properties. NLO activity increases with decreasing of EGAP values. The other significant parameters are absolute hardness, absolute softness and optical softness. Electron mobility increase with increasing of the softness. Therefore, NLO properties of investigated molecules increase with softness value. Other parameters are global electronegativity. Electron delocalization increases with decreasing of the absolute electronegativity. It can be said that NLO activity increases with decreasing of absolute electronegativity. Additional electronic charge and polarizability is the last parameters. Electronic charge is related to polarizability of molecule. The higher value of polarizability and additional electronic charge is the more active in NLO applications. According to above explanations, NLO property and activity of related compounds are listed as follow:
According to EHOMO: According to ELUMO: According to EGAP:
Enrofloxacin N Complex (3) N Complex (1) N Complex (2) N Urea Complex (3) N Complex (2) N Complex (1) N Enrofloxacin N Urea Complex (3) N Complex (2) N Complex (1) N Enrofloxacin N Urea
Table 6 Calculated QCDs of mentioned complexes in gas phase.
Urea Enrofloxacin Complex (1) Complex (2) Complex (3) a b c
In eV. In eV−1. In a.u.
EHOMOa
ELUMOa
EGAPa
ηa
σb
σOb
χa
ΔNmax
αc
−9.051 −7.513 −7.961 −8.049 −7.799
0.168 −1.093 −1.893 −2.094 −2.154
9.219 6.419 6.068 5.955 5.645
4.610 3.210 3.034 2.977 2.823
0.217 0.312 0.330 0.336 0.354
0.108 0.156 0.165 0.168 0.177
4.441 4.303 4.927 5.072 4.976
0.963 1.341 1.624 1.703 1.763
30.937 257.146 270.171 299.662 316.367
K. Sayin, A. Üngördü / Spectrochimica Acta Part A: Molecular and Biomolecular Spectroscopy 220 (2019) 117102
7
Fig. 6. Calculated MEP maps of mentioned compounds in gas phase.
According to η and σ: According to σO: According to χ: According to ΔNmax: According to α:
Complex (3) N Complex (2) N Complex (1) N Enrofloxacin N Urea Complex (3) N Complex (2) N Complex (1) N Enrofloxacin N Urea Enrofloxacin N Urea N Complex (1) N Complex (3) N Complex (2) Complex (3) N Complex (2) N Complex (1) N Enrofloxacin N Urea Complex (3) N Complex (2) N Complex (1) N Enrofloxacin N Urea
According to above ranking, complex (3) seems the most active molecule in respect NLO properties. Additionally, NLO activity of boron complexes are higher than that of enrofloxacin. It can be said that NLO activity increases with the complexation. MEP maps of related complexes and ciprofloxacin are calculated and represented in Fig. 6. According to Fig. 6, electron density on molecule surface is different from each other. Electron density is the highest in red regions. The red areas in complex (1) are higher than those of other. The reduction of the red region implies that there is electron delocalization on the molecule surface. It can be seen easily from Fig. 6, complex (3) has the most yellow and green areas. Therefore, it is expected that NLO activity of complex (3) is the highest. As a result, complex (3) is a good candidate for NLO application. 3.3. Biological activity and molecular docking calculations Determination biological re activity is so significant for the living. A lot of money and time is spent on such researches and there are still many problems to be investigated. Such investigations can be done by
computational chemistry. In this study, cis-platin and related compounds are investigated in water. Some quantum chemical descriptors are calculated and given in Table 7. Additionally, contour plots of HOMO and LUMO of studied complexes are represented in Fig. 7. QCDs in Table 7 never give exact result. However, reactivity tendency may learn from them. It has been explained in previous publications that the descriptors how affect the biological reactivity [37,38]. The biological reactivity ranking in each descriptor are given as follow: According to EHOMO: According to ELUMO: According to EGAP: According to η and σ: According to S: According to χ: According to CP: According to ω: According to N: According to ΔNmax:
Complex (1) N Complex (2) = Complex (3) N cis-platin Complex (3) N Complex (2) N Complex (1) N cis-platin Complex (3) N Complex (2) N Complex (1) N cis-platin Complex (3) N Complex (2) N Complex (1) N cis-platin Complex (3) N Complex (2) N Complex (1) N cis-platin cis-platin N Complex (1) N Complex (2) N Complex (3) cis-platin N Complex (1) N Complex (2) N Complex (3) Complex (1) N Complex (2) N Complex (3) N cis-platin Complex (1) N Complex (2) N Complex (3) N cis-platin Complex (3) N Complex (2) N Complex (1) N cis-platin
According to above rankings, biological reactivities of the boron complexes are higher than that of cis-platin. To learn exact effect in lung cancer, mentioned complexes are interacted with a proteins 2ITN and 2ITV. 2ITN and 2ITV are primary citation of related structures of lung cancer-derived egfr mutants [39]. Previous researches demonstrate that blocking of VEGFRTK is one of the anticancer mechanisms [40]. Therefore, the docking study is carried out to investigate the possible binding conformations for mentioned complexes to the (VEGFR) active binding site. Docking structures between 2ITN and mentioned complexes are represented in Fig. 8.
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K. Sayin, A. Üngördü / Spectrochimica Acta Part A: Molecular and Biomolecular Spectroscopy 220 (2019) 117102
Table 7 Calculated quantum chemical descriptors in water.
cis-Platin Complex (1) Complex (2) Complex (3)
cis-Platin Complex (1) Complex (2) Complex (3) a b
In eV. In eV−1.
EHOMOa
ELUMOa
EGAPa
Ηa
Σb
Sb
−8.513 −7.510 −7.538 −7.538
−0.577 −1.721 −1.858 −1.905
7.936 5.789 5.680 5.633
3.968 2.895 2.840 2.817
0.252 0.345 0.352 0.355
0.126 0.173 0.176 0.178
χa
CPa
ωa
Nb
ΔNmax
4.545 4.615 4.698 4.721
−4.545 −4.615 −4.698 −4.721
2.603 3.679 3.886 3.957
0.384 0.272 0.257 0.253
1.145 1.594 1.654 1.676
According to Fig. 8, there are two hydrogen bonds (“A-745:LYS-2HZ” – F and “A-844:LEU-CG” – F) between 2ITN and complex (1). The other dominant interactions are dipole – dipole interactions. Interaction energies are calculated as −491.9, −476.2, and −476.0 kJ mol−1 for complex (1), (2), and (3) as, respectively. Additionally, investigated complexes are interacted with 2ITV. Docking structures between 2ITV and mentioned complexes are represented in Fig. 9. According to Fig. 9, there is no any hydrogen bond between 2ITV and related complexes. Dipole – dipole interaction is dominant in these interactions. The interaction energies are calculated as −338.3, −341.7 and −343.6 kJ mol−1 for complex (1), (2) and (3), respectively. According to these results and QCD rankings, biological reactivity of complex (1) and (3) is near to each other. Both of compound can be used in anti-cancer drug to prevent lung cancer. Absorption, distribution, metabolism and excretion (ADME) are so important analyses in the drug development. ADME analyses are performed by using SwissADME
Fig. 7. Contour plots of HOMO and LUMO of studied complexes.
K. Sayin, A. Üngördü / Spectrochimica Acta Part A: Molecular and Biomolecular Spectroscopy 220 (2019) 117102
Complex (1)
9
Complex (2)
Complex (3)
Fig. 8. Receptor – ligand structures between 2ITN and studied complexes.
web tool (http://www.swissadme.ch/). The ADME results are given in Table 8. The physicochemical properties which are total polarized surface area (TPSA), molecular refractivity, molecular weight, number of Hbond acceptors, number of H-bond donors, and number of rotatable bonds are given in Table 8. These results are mainly similar to each other. However, molecular weight of complex (3) is higher than 500 g/mol. It is important for Lipinski parameters due to the fact that molecular weight should be lower than 500 g/mol respect to Lipinski rule. Lipinski is important in the determination of druglikeness of drug candidates. So, molecular weight of complex (3) is disadvantage for it. Additionally, the number of hydrogen bond acceptor in complex (1) is
more than those of others. It is gained an advantage for complex (1). Lipophilicity is important issue for drug candidates. Lipophilicity refers to the ability of compound to dissolve in fats, oils, lipids, and non-polar solvents. Lipophilicity can be given some predictions. But lipophilicity value is given by using consensus Log Po/w which is average of predictions. Lipophilicity value of complex (1) is the lowest one among the studied complexes while water solubility of complex (1) is the best. These results are important in the selection drug. Gastrointestinal absorption (GI Absorption) and blood-brain barrier permeant (BBB Permeant) are same in each studied complex. These results are the wanted ones from drugs. Cytochrome P450 (CYP) inhibitors which are CYP1A2, CYP2C19, CYP2C9, CYP2D6 and CYP3A4 don't want to be
Complex (1)
Complex (2)
Complex (3)
Fig. 9. Docking structures between 2ITV and studied complexes.
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Table 8 The ADME results of studied complexes. Parameter
Complex (1)
Complex (2)
Complex (3)
Parameter
Complex (1)
Complex (2)
Complex (3)
TPSA (Å2) Molar refractivity Molar weight (g/mol) Number of H-bond acceptors Number of H-bond donors Number of rotatable bonds Consensus log Po/w Log S Solubility (mg/mL) GI absorption
62.21 114.45 408.20 7 0 3 1.44 −4.23 2.38 × 10−2 High
62.21 123.94 441.11 5 0 3 1.61 −4.75 7.89 × 10−3 High
62.21 130.09 530.01 5 0 3 1.80 −5.51 1.63 × 10−3 High
BBB permeant CYP1A2 CYP2C19 CYP2C9 CYP2D6 CYP3A4 Log Kp (cm/s) Lipinksi Bioavailability score Synthetic accessibility
Yes No Yes No No Yes −6.64 Yes (5/5) 0.55 4.52
Yes No Yes No Yes Yes −6.49 Yes (5/5) 0.55 4.42
Yes No Yes No Yes Yes −6.79 Yes (4/5) 0.55 4.52
inhibited by drugs. According to our results, two CYP inhibitors are inhibited by complex (1) while three CYP inhibitors are inhibited by complex (2) and (3). So, complex (1) is found as the best drug candidate from ADME analyses. According to molecular docking and ADME analyses, complex (1) is selected as the best drug candidate for lung cancer.
4. Conclusions Some boron complexes with enrofloxacin are analyzed by computational methods. Enrofloxacin and its boron complexes are optimized at M062X/6-31+G(d) level in gas phase and water. The most stable conformer of enrofloxacin (isomer 5) is determined by thermodynamic parameters. Structural and spectral analyses isomer 5 are done. The boron complexes of enrofloxacin are investigated at same level of theory. Mentioned complexes are characterized by structural parameters, IR and NMR spectrum. In addition to these results, quantum chemical descriptors are calculated in gas phase and water. NLO activity are examined in vacuum and complex (3) is found as the best candidate for NLO application. Additionally, biological reactivity of mentioned complexes is investigated in water by calculating some QCDs. Molecular docking calculation of related complexes with 2ITN and 2 ITV are performed. Finally, ADME analyses are performed and as a result, complex (1) is determined as the best drug candidate for lung carcinoma.
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Contents lists available at ScienceDirect
Spectrochimica Acta Part A: Molecular and Biomolecular Spectroscopy journal homepage: www.elsevier.com/locate/saa
Investigations of structural, spectral and electronic properties of enrofloxacin and boron complexes via quantum chemical calculation and molecular docking Koray Sayin ⁎, Ayhan Üngördü Department of Chemistry, Faculty of Science, Sivas Cumhuriyet University, 58140 Sivas, Turkey
a r t i c l e
i n f o
Article history: Received 13 September 2018 Received in revised form 24 April 2019 Accepted 9 May 2019 Available online 11 May 2019 Keywords: Modelling studies Biological activity Molecular docking ADME NLO properties
a b s t r a c t Quantum chemical analyses were performed over enrofloxacin and boron complexes. The most stable isomer of enrofloxacin was examined at M062X/6-31+G(d) level in gas phase. Structural and spectral characterizations of enrofloxacin and its complexes were performed at same level of theory. MEP maps of studied compound were calculated via ESP charges analyses. Some quantum chemical descriptors (QCDs) were calculated to determine the non-linear optical (NLO) and biological reactivity of studied molecules. Furthermore, molecular docking calculations between boron complexes and a protein (ID: 2ITN and 2ITV) were done. ADME analyses were done in the determination of the best drug candidate. As a result, complex (3) was found as the best in the NLO applications and it was found that complex (1) and (3) have similar biological reactivity in lung cancer treatment. © 2019 Elsevier B.V. All rights reserved.
1. Introduction Fluoroquinolone is the member of quinolone family and this group is known as antibiotics. The antibiotics show their effect by preventing the deoxyribonucleic acid in the target cell. Antibiotics have both beneficial and detrimental effect to environment or livings [1–9]. Chemicals with boron atom have broad applications in many fields. Especially, these compounds attract the attention with their applications in optics and medicine. In recent years, importance of boron mineral in medicine is increasing. In the treatment, patient cells are selected and destroyed, and healthy cells are damaged to a minimum level. In this study, 1cyclopropyl-7-(4-ethylpiperazin-1-yl)-6-fluoro-4-oxo-1,4dihydroquinoline-3-carboxylic acid (enrofloxacin) and its boron complexes are investigated via quantum chemical calculations. Investigations over some boron complexes with enrofloxacin which are represented in Scheme 1 are performed. Complex (1) has been synthesized by Wang et al. and there is not structural data in their paper [10]. Quantum chemical calculations of similar boron complexes have been published by Sayin and coworkers [11,12]. Enrofloxacin and its boron complexes are investigated in detail in this paper. M06-2X/6-31+G(d) level has been found as the ⁎ Corresponding author. E-mail address: [email protected] (K. Sayin). E-mail address: [email protected] (K. Sayin).
https://doi.org/10.1016/j.saa.2019.05.007 1386-1425/© 2019 Elsevier B.V. All rights reserved.
best calculation level for this type compounds [11,12]. Therefore, same level of theory is used in this study. Firstly, enrofloxacin is examined in detail. Conformational analyses of enrofloxacin are performed in this paper. The most stable isomer for enrofloxacin is determined by using thermodynamic parameters, total energy (ETotal), enthalpy (H), and Gibbs free energy (G). Structural and spectral (IR and NMR) analyses of the most stable isomer are performed. Enrofloxacin is deprotonated and re-optimized at same level of theory. Then molecular electrostatic potential (MEP) map of it is calculated via electro-static potential (ESP) charges to determine the electro-rich regions to coordinate with boron. The last part of this paper is the boron complexes. Mentioned complexes are optimized at same level of theory in gas phase and water. IR spectrum of studied boron complexes are calculated and examined by using VEDA 4XX program. Chemical shift values of carbon and hydrogen atoms are calculated against tetramethylsilane. MEP maps of related boron complexes are investigated in gas phase and water. Some quantum chemical descriptors (QCDs) are calculated in gas phase to investigate non-linear optical (NLO) properties. Finally, some QCDs are re-calculated in water to investigate the biological properties. Enrofloxacin and its boron complexes are interacted with 2ITN and 2ITV target cell by molecular docking calculations. So, the best drug candidate for lung cancer is determined by using interaction energies. Additionally, Absorption, distribution, metabolism and excretion (ADME) analyses are performed for studied complexes. The best drug respect to physicochemical, lipophilicity, water solubility,
2
K. Sayin, A. Üngördü / Spectrochimica Acta Part A: Molecular and Biomolecular Spectroscopy 220 (2019) 117102 Table 1 Mentioned thermodynamic parameters of each isomer. Isomers 1 2 3 4 5 6 a
Scheme 1. Schematic diagram of investigated boron complexes with atomic labelling. R: -F− (1), -Cl− (2), and -Br− (3).
ETotala
Ha
Ga
−769,413.72 −769,414.06 −769,413.24 −769,421.44 −769,421.79 −769,420.98
−769,413.13 −769,413.47 −769,412.65 −769,420.85 −769,421.20 −769,420.39
−769,461.03 −769,461.33 −769,461.09 −769,468.03 −769,468.50 −769,467.98
In kcal/mol.
the lowest unoccupied molecular orbital (ELUMO), ionization energy (I), electron affinity (A), energy gap (EGAP), absolute hardness (η), absolute softness (σ), optical softness (σO), global softness (S), absolute electronegativity (χ), chemical potential (CP), electrophilicity index (ω), nucleophilicity index (N), additional electronic charges (ΔNMax) and polarizability (α) were used as QCDs. EHOMO, ELUMO and α were directly taken from calculation results. The other descriptors were calculated by using Eqs. (1)–(9) [18–20]. I ¼ −EHOMO
ð1Þ
pharmacokinetics, druglikeness and medicinal chemistry properties are determined in detail.
A ¼ −ELUMO
ð2Þ
2. Calculation method
EGAP ¼ ELUMO −EHOMO
ð3Þ
Molecular simulation calculations were performed by Gaussian package program [12–15]. Input file of enrofloxacin and the boron complexes were prepared by using ChemDraw Professional 15.1 and GausView 5.0.8 programs [16]. Pre-calculations and full-calculations were performed by using Gaussian IA32W-G09RevA.02 and Gaussian AS64L-G09RevD.01 programs, respectively. Investigated compounds were re-optimized by using M06-2X method, one of the hybrid density functional theory (DFT) functions, with 6-31+G(d) basis set in gas phase and water. For calculation in water, conductor like polarized continuum model (C-PCM) was taken into consideration in solute – solvent interactions. Some conformational structures of enrofloxacin were drawn and optimized at same level of theory. The most stable conformer was determined by thermodynamic parameters. MEP map and contour of it were calculated and examined in detail. Boron was coordinated to it from electrophilic regions. VEDA 4XX program was used in the determination of vibration modes in studied complexes [17]. Additionally, tetramethylsilane was used as a reference substance for carbon and hydrogen atoms. Some quantum chemical descriptors which are energy of the highest occupied molecular orbital (EHOMO), energy of
η¼
I−A ELUMO −EHOMO ¼ 2 2
ð4Þ
σ¼
1 η
ð5Þ
σO ¼
χ¼
1 EGAP
jI þ Aj j−EHOMO −ELUMO j ¼ 2 2
ð6Þ
ð7Þ
CP ¼ −χ
ð8Þ
CP ΔNMax ¼ − η
ð9Þ
CP2 2η
ð10Þ
ω¼
Scheme 2. Schematic diagram of conformer of ciprofloxacin.
K. Sayin, A. Üngördü / Spectrochimica Acta Part A: Molecular and Biomolecular Spectroscopy 220 (2019) 117102
3
Fig. 1. Optimized structure of enrofloxacin.
Fig. 2. Calculated IR spectrum for enrofloxacin.
1 N¼ ω S¼
1 2η
ð11Þ
ð12Þ
In addition to them, Chemissian Version 4.43 was used in taking images of MOED [21]. Chemcraft Version 1.8 was used in interpreting of NMR spectrums [22]. Molecular docking calculations are done by using Hex program (Version:8.0.0) [23]. Finally, ADME analysis were done by using SwissADME web tool [24]. 3. Result and discussion 3.1. Analyses of enrofloxacin Schematic diagram of enrofloxacin and isomers are shown in Scheme 2. The most stable isomer is determined by using thermodynamic parameters which are total energy (ETotal), enthalpy (H) and Gibbs free energy (G). All calculations are performed at M06-2X/6-31 +(d) level in gas phase and obtained results are given in Table 1.
Table 2 Calculated NMR results of mentioned molecule at M062X/6-31+G(d) level. 13
1
C NMR results
C2 C4 C5 C6 C8 C9 C10 C11 C12 C13 C17 C18 C20 C21 C22 C23 C24 C25 C26
169.2 186.6 123.5 159.5 147.8 135.1 126.9 157.6 154.2 116.8 53.6 51.5 55.4 52.1 36.7 12.0 7.2 55.5 15.0
H NMR results
O1H C6H C10H C13H C17H C17H″ C18H C18H″ C20H C20H′ C21H C21H′ C22H C23H C23H′ C24H C24H′ C26H C26H′ C27H C27H′ C27H″
11.9 9.1 8.4 7.8 4.1 3.3 2.7 1.9 3.0 2.7 3.8 3.6 3.0 1.1 0.8 1.4 1.4 2.5 1.9 1.2 1.1 1.0
4
K. Sayin, A. Üngördü / Spectrochimica Acta Part A: Molecular and Biomolecular Spectroscopy 220 (2019) 117102
Fig. 3. Optimized structure and MEP map of deprotonated enrofloxacin.
Fig. 4. Optimized structures of studied boron complexes with ciprofloxacin in gas phase.
According to Table 1, isomer 5 has the lowest ETotal, H and G. This result show that the most stable structure is isomer 5. This molecule is taken into account for other calculations. Optimized structure and atomic labelling of isomer 5 are represented in Fig. 1. IR spectrum of isomer 5 is calculated to characterize the molecular structure. Calculated IR spectrum and harmonic frequencies of some selected peaks are represented in Fig. 2. The calculated frequencies are harmonic values while frequencies obtained via experimentally techniques are anharmonic values. Due to the fact that, there may be some differences between calculated and experimental frequencies. As experimentally, OH stretching frequencies have been calculated in the range of 3250–3730 cm−1 [25–27]; 1578–1730 cm−1 for C_O stretching frequencies [28–31]; 1400–1575 cm−1 for C_C stretching frequencies [32,33] and 1251–1614 cm−1 for C_N stretching frequencies [33]. According to these data, the calculated frequencies are in the agreement with published frequencies. NMR spectrum of isomer 5 is calculated to calculate the chemical shift values of carbon and hydrogen atoms. Chemical shift values of carbon and hydrogen atoms are given in Table 2. According to Table 1, chemical shift values of aliphatic carbon atoms are calculated in the range of 7–55 ppm; 116–186 ppm for aromatic carbon atoms; 7.8–9.1 ppm for aliphatic hydrogen atoms and 0.8–4.1 ppm for aromatic hydrogen atoms. Enrofloxacin is deprotonated from OH proton in carboxyl group of ciprofloxacin ligand. Optimized structure at the same level of obtained anion is given in Fig. 3. MEP maps are calculated at the same level of theory and represented in Fig. 3.
According to MEP map in Fig. 3., there is red area at environment of oxygen atoms (especially in carboxyl group). Electron density is higher in this region than others. These regions are appropriate for nucleophilic attack. Table 3 Some geometric parameters belong to mentioned molecules at M062X/6-31+G(d) level in vacuo. Assignments
Complex (1)
Complex (2)
Complex (3)
Bond length (Å) B-R1′ B-R2′ B-O1 B-O15 C2-O3 C4-O15 C11-F14 N7-C22
1.381 1.358 1.476 1.551 1.212 1.280 1.345 1.450
1.871 1.818 1.458 1.517 1.209 1.288 1.344 1.451
2.051 1.967 1.451 1.502 1.208 1.292 1.343 1.452
Bond angle (deg.) R1′-B-R2′ R1′-B-O1 R1′-B-O15 R2′-B-O1 R2′-B-O15 O1-B-O15 O1-C2-O3 O1-C2-C5 O15-C4-C5
114.90 110.13 104.99 110.55 106.95 108.99 124.85 114.42 121.99
113.46 109.56 105.25 110.37 107.59 110.48 124.31 114.30 121.84
114.29 108.95 103.75 110.82 108.03 110.80 124.13 114.24 121.74
K. Sayin, A. Üngördü / Spectrochimica Acta Part A: Molecular and Biomolecular Spectroscopy 220 (2019) 117102
5
1 2 8
3 7 4
6
5
(1) 1 2 3 6
4
7
5
(2) 1 2 3 6
4
7
5
(3) Fig. 5. IR spectrum of mentioned complexes at M062X/6-31+G(d) level in gas phase.
3.2. Boron complexes
Table 4 Analysis of IR spectrum. Peak assignments
Frequency (cm−1)
Vibration modesa
In complex (1) 1 2 3 4 5 6 7 8
3112 2968 1855 1716 1566 1280 1116 938
S (aliphatic CH) S (aliphatic CH) S (C=O) S (C=O) S (C=N) and B (H-C-C) S (B-F′) S (B-F′) and S (B\ \O) S (B\ \O), B (C-C-C in ring) and B (O-C-O)
In complex (2) 1 2 3 4 5 6 7
3115 2964 1862 1716 1563 1310 900
S (aliphatic CH) S (aliphatic CH) S (C=O) S (C=O) and S (C=N) S (C=O) and B (H-C-C) S (C\ \F) S (B-Cl′), B (B-O-C) and O (Cl-O-O-B)
In complex (3) 1 2 3 4 5 6 7
3114 2977 1863 1718 1559 1306 900
S (aliphatic CH) S (aliphatic CH) S (C=O) S (C=O) and S (C=N) S (C=O) and B (H-C-C) S (C\ \O) S (B-Br′) and B (B-O-C)
a
Vibration Modes: S: Stretching; B: Bending; O: Out.
3.2.1. Optimization and spectral analyses The boron complexes are optimized at M06-2X/6-31+G(d) level in gas phase and water. Optimized structures are represented in Fig. 4 and some geometric parameters are given in Table 3. The bond lengths between boron and halogens are calculated in the range of 1.35–2.05 Å. As for the published data, these bond lengths have been reported in the range of 1.36–2.0 Å [34]. Additionally, the B\\O bond length is calculated in the range of 1.45–1.55 Å while it has been reported in the range of 1.40–1.60 Å [35,36]. According to these values, the calculated results are in the agreement with published results. Bond angles environment of boron atom are calculated as nearly 1100. This result implies the geometric structure of environment of center atom is distorted tetrahedral in each studied complex. Spectral analyses (IR and NMR) are done for each complex. IR spectrum of the boron complexes are calculated at same level of theory in gas phase and given in Fig. 5. Some peaks are labelled in IR spectrum and they are examined by VEDA 4XX program and given in Table 4. For complex (1), stretching frequencies of “C=O” bond, “C= Opyridine” bond “B-F” and “B-O” have been reported as 1716 (1855)calculated; 1635 (1716)calculated; 1148 (1280)calculated and 1053 (1116)calculated, respectively. There are some differences between experimental and calculated results due to the harmonic and anharmonic properties. Generally, there is a good agreement between experimental and calculated results. Chemical shift values of carbon and hydrogen atoms are calculated to get data about complex structures. Tetramethylsilane and
6
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Table 5 Chemical shift values of carbon and hydrogen atoms in mentioned complexes. 13
1
C NMR
H NMR
Assignments
Comp. (1)
Comp. (2)
Comp. (3)
Assignments
Comp. (1)
Comp. (2)
Comp. (3)
C2 C4 C5 C6 C8 C9 C10 C11 C12 C13 C17 C18 C20 C21 C22 C23 C24 C25 C26 – –
164.8 185.4 122.9 160.3 147.9 127.3 126.8 159.5 156.6 115.2 54.5 52.3 54.0 51.4 37.2 11.9 8.5 56.6 13.9 – –
162.9 182.8 122.2 159.1 148.4 126.5 127.7 158.5 157.7 115.5 53.9 51.4 54.3 51.8 38.0 11.3 9.0 56.0 14.1 – –
163.1 184.9 124.9 158.5 148.2 146.3 125.1 160.7 157.7 115.2 53.1 51.4 55.3 52.0 37.0 11.3 10.1 54.3 14.8 – –
C6H C10H C13H C17H C17H′ C18H C18H′ C20H C20H′ C21H C21H′ C22H C23H C23H′ C24H C24H′ C25H C25H′ C26H C26H′ C26H″
9.1 8.9 7.9 4.2 3.5 2.9 1.6 2.8 2.4 3.7 3.6 3.2 1.3 0.8 1.5 1.5 2.3 1.8 1.3 1.2 1.1
9.2 8.9 7.9 4.1 3.5 3.0 1.5 2.9 2.6 3.7 3.7 3.4 1.4 0.8 1.6 1.4 2.3 1.9 1.2 1.1 1.1
9.3 9.0 8.0 4.0 3.6 4.0 1.8 3.0 2.8 3.8 3.7 3.4 1.5 0.8 1.7 1.3 2.5 2.0 1.2 1.1 1.0
trichlorofluoromethane is used as reference substance for carbon/hydrogen and fluorine atoms, respectively. NMR spectrum of studied complexes are calculated at M062X/6-31+G(d) level in gas phase. Chemical shift values of carbon and hydrogen atoms are given in Table 5. These results are in agreement with theoretical expectation and published articles. The chemical shift values are calculated in the range of 8.5–56.6 ppm and 115.2–185.4 ppm for aliphatic and aromatic carbon atoms, respectively. Chemical shift values of hydrogen atoms which are coordinated to aliphatic and aromatic carbon atoms are calculated as in the range of 1.0–4.2 ppm and 7.9–9.3 ppm, respectively. 3.2.2. Non-linear optical (NLO) activity NLO activities are important for telecommunication industry. NLO activity increases with the increasing of molecular planarity and π electron delocalization. Furthermore, some QCDs can be used in the determination of NLO properties. QCDs to be examined are energy of the highest occupied molecular orbital (EHOMO), energy of the lowest unoccupied molecular orbital (ELUMO), ionization energy (I), electron affinity (A), energy gap (EGAP), absolute hardness (η), absolute softness (σ), optical softness (σO), absolute electronegativity (χ), additional electronic charges (ΔNMax) and polarizability (α). Mentioned QCDs of enrofloxacin and its boron complexes are calculated in gas phase by using Eqs. (1)–(9) and given in Table 6. The first parameter is the EHOMO. If its energy is high, compounds may give electron more easily. It implies that NLO properties and activities increases with increasing of the energy of HOMO. Second
parameter is the energy of LUMO. If the ELUMO value is low, compounds can accept electrons and this result shows that non-linear optical activity of studied compounds increase with decreasing of ELUMO. Third parameter is energy gap between frontier molecular orbitals. Electron freedom is significant in determination of NLO properties. NLO activity increases with decreasing of EGAP values. The other significant parameters are absolute hardness, absolute softness and optical softness. Electron mobility increase with increasing of the softness. Therefore, NLO properties of investigated molecules increase with softness value. Other parameters are global electronegativity. Electron delocalization increases with decreasing of the absolute electronegativity. It can be said that NLO activity increases with decreasing of absolute electronegativity. Additional electronic charge and polarizability is the last parameters. Electronic charge is related to polarizability of molecule. The higher value of polarizability and additional electronic charge is the more active in NLO applications. According to above explanations, NLO property and activity of related compounds are listed as follow:
According to EHOMO: According to ELUMO: According to EGAP:
Enrofloxacin N Complex (3) N Complex (1) N Complex (2) N Urea Complex (3) N Complex (2) N Complex (1) N Enrofloxacin N Urea Complex (3) N Complex (2) N Complex (1) N Enrofloxacin N Urea
Table 6 Calculated QCDs of mentioned complexes in gas phase.
Urea Enrofloxacin Complex (1) Complex (2) Complex (3) a b c
In eV. In eV−1. In a.u.
EHOMOa
ELUMOa
EGAPa
ηa
σb
σOb
χa
ΔNmax
αc
−9.051 −7.513 −7.961 −8.049 −7.799
0.168 −1.093 −1.893 −2.094 −2.154
9.219 6.419 6.068 5.955 5.645
4.610 3.210 3.034 2.977 2.823
0.217 0.312 0.330 0.336 0.354
0.108 0.156 0.165 0.168 0.177
4.441 4.303 4.927 5.072 4.976
0.963 1.341 1.624 1.703 1.763
30.937 257.146 270.171 299.662 316.367
K. Sayin, A. Üngördü / Spectrochimica Acta Part A: Molecular and Biomolecular Spectroscopy 220 (2019) 117102
7
Fig. 6. Calculated MEP maps of mentioned compounds in gas phase.
According to η and σ: According to σO: According to χ: According to ΔNmax: According to α:
Complex (3) N Complex (2) N Complex (1) N Enrofloxacin N Urea Complex (3) N Complex (2) N Complex (1) N Enrofloxacin N Urea Enrofloxacin N Urea N Complex (1) N Complex (3) N Complex (2) Complex (3) N Complex (2) N Complex (1) N Enrofloxacin N Urea Complex (3) N Complex (2) N Complex (1) N Enrofloxacin N Urea
According to above ranking, complex (3) seems the most active molecule in respect NLO properties. Additionally, NLO activity of boron complexes are higher than that of enrofloxacin. It can be said that NLO activity increases with the complexation. MEP maps of related complexes and ciprofloxacin are calculated and represented in Fig. 6. According to Fig. 6, electron density on molecule surface is different from each other. Electron density is the highest in red regions. The red areas in complex (1) are higher than those of other. The reduction of the red region implies that there is electron delocalization on the molecule surface. It can be seen easily from Fig. 6, complex (3) has the most yellow and green areas. Therefore, it is expected that NLO activity of complex (3) is the highest. As a result, complex (3) is a good candidate for NLO application. 3.3. Biological activity and molecular docking calculations Determination biological re activity is so significant for the living. A lot of money and time is spent on such researches and there are still many problems to be investigated. Such investigations can be done by
computational chemistry. In this study, cis-platin and related compounds are investigated in water. Some quantum chemical descriptors are calculated and given in Table 7. Additionally, contour plots of HOMO and LUMO of studied complexes are represented in Fig. 7. QCDs in Table 7 never give exact result. However, reactivity tendency may learn from them. It has been explained in previous publications that the descriptors how affect the biological reactivity [37,38]. The biological reactivity ranking in each descriptor are given as follow: According to EHOMO: According to ELUMO: According to EGAP: According to η and σ: According to S: According to χ: According to CP: According to ω: According to N: According to ΔNmax:
Complex (1) N Complex (2) = Complex (3) N cis-platin Complex (3) N Complex (2) N Complex (1) N cis-platin Complex (3) N Complex (2) N Complex (1) N cis-platin Complex (3) N Complex (2) N Complex (1) N cis-platin Complex (3) N Complex (2) N Complex (1) N cis-platin cis-platin N Complex (1) N Complex (2) N Complex (3) cis-platin N Complex (1) N Complex (2) N Complex (3) Complex (1) N Complex (2) N Complex (3) N cis-platin Complex (1) N Complex (2) N Complex (3) N cis-platin Complex (3) N Complex (2) N Complex (1) N cis-platin
According to above rankings, biological reactivities of the boron complexes are higher than that of cis-platin. To learn exact effect in lung cancer, mentioned complexes are interacted with a proteins 2ITN and 2ITV. 2ITN and 2ITV are primary citation of related structures of lung cancer-derived egfr mutants [39]. Previous researches demonstrate that blocking of VEGFRTK is one of the anticancer mechanisms [40]. Therefore, the docking study is carried out to investigate the possible binding conformations for mentioned complexes to the (VEGFR) active binding site. Docking structures between 2ITN and mentioned complexes are represented in Fig. 8.
8
K. Sayin, A. Üngördü / Spectrochimica Acta Part A: Molecular and Biomolecular Spectroscopy 220 (2019) 117102
Table 7 Calculated quantum chemical descriptors in water.
cis-Platin Complex (1) Complex (2) Complex (3)
cis-Platin Complex (1) Complex (2) Complex (3) a b
In eV. In eV−1.
EHOMOa
ELUMOa
EGAPa
Ηa
Σb
Sb
−8.513 −7.510 −7.538 −7.538
−0.577 −1.721 −1.858 −1.905
7.936 5.789 5.680 5.633
3.968 2.895 2.840 2.817
0.252 0.345 0.352 0.355
0.126 0.173 0.176 0.178
χa
CPa
ωa
Nb
ΔNmax
4.545 4.615 4.698 4.721
−4.545 −4.615 −4.698 −4.721
2.603 3.679 3.886 3.957
0.384 0.272 0.257 0.253
1.145 1.594 1.654 1.676
According to Fig. 8, there are two hydrogen bonds (“A-745:LYS-2HZ” – F and “A-844:LEU-CG” – F) between 2ITN and complex (1). The other dominant interactions are dipole – dipole interactions. Interaction energies are calculated as −491.9, −476.2, and −476.0 kJ mol−1 for complex (1), (2), and (3) as, respectively. Additionally, investigated complexes are interacted with 2ITV. Docking structures between 2ITV and mentioned complexes are represented in Fig. 9. According to Fig. 9, there is no any hydrogen bond between 2ITV and related complexes. Dipole – dipole interaction is dominant in these interactions. The interaction energies are calculated as −338.3, −341.7 and −343.6 kJ mol−1 for complex (1), (2) and (3), respectively. According to these results and QCD rankings, biological reactivity of complex (1) and (3) is near to each other. Both of compound can be used in anti-cancer drug to prevent lung cancer. Absorption, distribution, metabolism and excretion (ADME) are so important analyses in the drug development. ADME analyses are performed by using SwissADME
Fig. 7. Contour plots of HOMO and LUMO of studied complexes.
K. Sayin, A. Üngördü / Spectrochimica Acta Part A: Molecular and Biomolecular Spectroscopy 220 (2019) 117102
Complex (1)
9
Complex (2)
Complex (3)
Fig. 8. Receptor – ligand structures between 2ITN and studied complexes.
web tool (http://www.swissadme.ch/). The ADME results are given in Table 8. The physicochemical properties which are total polarized surface area (TPSA), molecular refractivity, molecular weight, number of Hbond acceptors, number of H-bond donors, and number of rotatable bonds are given in Table 8. These results are mainly similar to each other. However, molecular weight of complex (3) is higher than 500 g/mol. It is important for Lipinski parameters due to the fact that molecular weight should be lower than 500 g/mol respect to Lipinski rule. Lipinski is important in the determination of druglikeness of drug candidates. So, molecular weight of complex (3) is disadvantage for it. Additionally, the number of hydrogen bond acceptor in complex (1) is
more than those of others. It is gained an advantage for complex (1). Lipophilicity is important issue for drug candidates. Lipophilicity refers to the ability of compound to dissolve in fats, oils, lipids, and non-polar solvents. Lipophilicity can be given some predictions. But lipophilicity value is given by using consensus Log Po/w which is average of predictions. Lipophilicity value of complex (1) is the lowest one among the studied complexes while water solubility of complex (1) is the best. These results are important in the selection drug. Gastrointestinal absorption (GI Absorption) and blood-brain barrier permeant (BBB Permeant) are same in each studied complex. These results are the wanted ones from drugs. Cytochrome P450 (CYP) inhibitors which are CYP1A2, CYP2C19, CYP2C9, CYP2D6 and CYP3A4 don't want to be
Complex (1)
Complex (2)
Complex (3)
Fig. 9. Docking structures between 2ITV and studied complexes.
10
K. Sayin, A. Üngördü / Spectrochimica Acta Part A: Molecular and Biomolecular Spectroscopy 220 (2019) 117102
Table 8 The ADME results of studied complexes. Parameter
Complex (1)
Complex (2)
Complex (3)
Parameter
Complex (1)
Complex (2)
Complex (3)
TPSA (Å2) Molar refractivity Molar weight (g/mol) Number of H-bond acceptors Number of H-bond donors Number of rotatable bonds Consensus log Po/w Log S Solubility (mg/mL) GI absorption
62.21 114.45 408.20 7 0 3 1.44 −4.23 2.38 × 10−2 High
62.21 123.94 441.11 5 0 3 1.61 −4.75 7.89 × 10−3 High
62.21 130.09 530.01 5 0 3 1.80 −5.51 1.63 × 10−3 High
BBB permeant CYP1A2 CYP2C19 CYP2C9 CYP2D6 CYP3A4 Log Kp (cm/s) Lipinksi Bioavailability score Synthetic accessibility
Yes No Yes No No Yes −6.64 Yes (5/5) 0.55 4.52
Yes No Yes No Yes Yes −6.49 Yes (5/5) 0.55 4.42
Yes No Yes No Yes Yes −6.79 Yes (4/5) 0.55 4.52
inhibited by drugs. According to our results, two CYP inhibitors are inhibited by complex (1) while three CYP inhibitors are inhibited by complex (2) and (3). So, complex (1) is found as the best drug candidate from ADME analyses. According to molecular docking and ADME analyses, complex (1) is selected as the best drug candidate for lung cancer.
4. Conclusions Some boron complexes with enrofloxacin are analyzed by computational methods. Enrofloxacin and its boron complexes are optimized at M062X/6-31+G(d) level in gas phase and water. The most stable conformer of enrofloxacin (isomer 5) is determined by thermodynamic parameters. Structural and spectral analyses isomer 5 are done. The boron complexes of enrofloxacin are investigated at same level of theory. Mentioned complexes are characterized by structural parameters, IR and NMR spectrum. In addition to these results, quantum chemical descriptors are calculated in gas phase and water. NLO activity are examined in vacuum and complex (3) is found as the best candidate for NLO application. Additionally, biological reactivity of mentioned complexes is investigated in water by calculating some QCDs. Molecular docking calculation of related complexes with 2ITN and 2 ITV are performed. Finally, ADME analyses are performed and as a result, complex (1) is determined as the best drug candidate for lung carcinoma.
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