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11DOI: 10.6060/ivkkt.20186112.5846 УДК: 544.127+544.187
КОНФОРМАЦИОННОЕ ПОВЕДЕНИЕ ГИДРАЗОНА, ПРОИЗВОДНОГО ПИРИДОКСАЛЬ-5-ФОСФАТА И ИЗОНИАЗИДА
А.Е. Погонин, Г.А. Гамов, М.Н. Завалишин, В.А. Шарнин
Александр Евгеньевич Погонин
Кафедра керамики и наноматериалов, Ивановский государственный химико-технологический университет, Шереметевский просп., 7, Иваново, Российская Федерация, 153000 E-mail: pogoninalexander@mail.ru
Георгий Александрович Гамов*, Максим Николаевич Завалишин, Валентин Аркадьевич Шарнин Кафедра общей химической технологии, Ивановский государственный химико-технологический университет, Шереметевский просп., 7, Иваново, Российская Федерация, 153000 E-mail: georgegamov38@gmail.com *, zavalishin00@gmail.com, sharn@isuct.ru
Гидразоны, производные пиридоксаля либо пиридоксаль-5-фосфата или гетероциклических гидразидов, представляют интерес, благодаря своей потенциальной биологической активности и возможности использования в качестве сенсоров на ионы металлов. Эти свойства гидразонов могут зависеть от конформационных равновесий молекулы, поскольку наиболее стабильный конформер может отличаться от формы с наибольшим сродством к биомолекуле либо иону металла. В настоящей работе депро-тонированный гидразон, производный пиридоксаль-5-фосфата и изониазида (PLP-INH3), исследован методами квантовой химии. Для этого гидразона возможны 3 различных вращения, приводящих к 8 конформерам, однако 4 из них, полученные при вращении пиридинового кольца остатка изониазида, являются вырожденными. С использованием теории функционала плотности (B3LYP/6-311++G(d,p)) были оптимизированы геометрические характеристики различных невырожденных конформеров вращения данного гидразона (различающихся взаимной ориентацией карбонильной группы остатка изони-азида и атома кислорода в положении 3 остатка PLP), а также оценены активацион-ные барьеры переходов между ними. Обсуждаются изменения в энергии и строении кон-формеров, а также переходных состояний. Количественный QTAIM (Quantum Theory of Atoms in Molecules) анализ был проведен с целью проверки наличия внутримолекулярных водородных связей. Формы гидразона, способные образовывать комплекс с ионами металлов, отличаются от наиболее устойчивых (по величинам полной энергии) конфор-меров. Была проведена предварительная оценка биологической активности гидразона PLP-INH3', а также молекулярный докинг для гидразона и киназы G-белок сопряженного рецептора. Определена предпочтительная конформация для связывания лиганда с активным сайтом киназы.
Ключевые слова: пиридоксаль-5-фосфат, изониазид, гидразон, конформер, активационный барьер
CONFORMATIONAL BEHAVIOR OF HYDRAZONE DERIVED FROM PYRIDOXAL 5'-PHOSPHATE AND ISONIAZID
A.E. Pogonin, G.A. Gamov, M.N. Zavalishin, V.A. Sharnin
Aleksandr E. Pogonin
Department of Ceramics and Nanomaterials Technology, Ivanono State University of Chemistry and Technology,
Sheremetevskiy ave., 7, Ivanovo, 153000, Russia
E-mail: pogoninalexander@mail.ru
George A. Gamov*, Maksim N. Zavalishin, Valentin A. Sharnin
Department of General Chemical Technology, Ivanovo State University of Chemistry and Technology,
Sheremetievskiy ave., 7, Ivanovo, 153000, Russia
E-mail: georgegamov38@gmail.com*, zavalishin00@gmail.com, sharn@isuct.ru
The hydrazones derived from pyridoxal or pyridoxal 5'-phosphate and heterocyclic hy-drazides are of interest due to their potential biological activity and metal sensing properties. These characteristics of hydrazones could be dependent on the conformation equilibria of molecule since the most stable conformer could differ from the one with the highest affinity towards biomolecule or metal ion. In the present contribution, deprotonated hydrazone formed by pyridoxal 5'-phosphate and isoniazid (PLP-INH3) was studied by means of quantum chemistry. Three rotations leading to eight conformers are possible for this hydrazone; however, four of those species obtained by rotation of pyridine ring of isoniazid residue are degenerated. The geometry of different non-degenerated rotation conformers of the hydrazine (differing by the mutual arrangement of carbonyl group of the isoniazid residue and oxygen in 3'-site of PLP moiety) was optimized using density functional theory (B3LYP/6-311++G(d,p)). Activation barriers were evaluated. Changes in energy and geometry of conformers as well as transition states are discussed. Quantitative QTAIM (Quantum Theory of Atoms in Molecules) analysis was performed in order to check the intermolecular hydrogen bonding existence. The species capable of forming the complex with the metal ions differs from the most stable (according to the total energy values) conformer. The preliminary prediction of biological activity of PLP-INH3- hydrazone and the docking for the hydrazone and G-protein-coupled receptor kinase were performed and the preferable conformation for ligand binding to the kinase active site was found.
Key words: pyridoxal 5'-phosphate, isoniazid, hydrazone, conformer, activation barrier
Для цитирования:
Погонин А.Е., Гамов Г.А., Завалишин М.Н., Шарнин В.А. Конформационное поведение гидразона,производного
пиридоксаль-5-фосфата и изониазида. Изв. вузов. Химия и хим. технология. 2018. Т. 61. Вып. 12. С. 101-107 For citation:
Pogonin A.E., Gamov G.A., Zavalishin M.N., Sharnin V.A. Conformational behavior of hydrazone derived from pyridoxal
5'-phosphate and isoniazid. Izv. Vyssh. Uchebn. Zaved. Khim. Khim. Tekhnol. 2018. V. 61. N 12. P. 101-107
INTRODUCTION
Hydrazones of different composition and structure are of great interest for researchers due to the wide range of their possible applications. They could be used in analytical chemistry as sensors for anions and metal ions [1, 2], antibacterial and antifungal agents [2, 3], catalysts [3], molecular machines brakes and switches [1], which are sensitive to the changes in pH and UV-irradiation. Hydrazone derived from pyridoxal 5'-phosphate and isoniazid (PLP-INH) is the closest analog of pyridoxal isonicotinoyl
hydrazone, the low-toxic chemical, which has been found to possess the membranotropic [4], antioxidant [5], demetalling towards iron [6], copper [7, 8] properties. PLP-INH hydrazone has been previously found to bind cobalt(II,III), nickel(II) ions [9] as well as to inhibit the copper(II)-mediated oxidation of ascor-bate [10].
Either coordination behavior or biological activity of hydrazone may depend on the conformation equilibria in the solution since the species may differ significantly in total energy and capability of binding the metal ions or biomolecules. Conformation free-
dom for the studied hydrazone is associated with the different molecular fragments ability to rotate around single (or partially double) bonds (Fig. 1).
Fig. 1. Structure of PLP-INH3- (DU conformer). Arrows show possible rotations leading to the different conformers Рис. 1. Структура PLP-INH3-. Стрелки указывают возможные направления вращения, приводящие к разным конформерам
The фз rotation (Fig. 1) could possibly make the same structure, however, it has to be confirmed. Mutual arrangement of 12 oxygen in the site 3 of pyridoxal 5'-phosphate residue and carbonyl group of isoniazid residue relative to the conditional line passing through the hydrazone molecule is used for the different conformers naming (Fig. 1). For example, in the scheme of the DU conformer (Fig. 1), atom O12 is located below (D - down) the chain C13-N23-N24-C26 and atom O27 is located above (U - up) the chain. Other possible structures are DD, UD, UU.
Therefore, the aim of the present contribution is to study the different conformers of PLP-INH formed as a result of the rotation ф1, ф2, фз. Quantum chemical calculations (DFT) were chosen as the method of preliminar study since it would allow finding the differences between conformers, which, in turn, could help to chose the experimental method for further investigations. The fully deprotonated hydrazone (PLP-INH3-) was studied only since these species could be predominant in the biological fluids basing on the lg Ka values [11]. Е-isomer has been considered only.
CALCULATIONS METHODS
The quantum chemical calculations were performed using Gaussian09 software [12] within the framework of density functional theory. The functional of B3LYP and basis set of 6-311G++(d,p) [13] were employed in order to optimize the geometry of different PLP-INH3- species and transition states. The suggested ground and transition states were verified by frequency analysis after optimization. The solvent
(water) was set within the framework of CPCM approach [14] in all cases. In order to study the internal rotations 91, 92, 93, potential energy surface (PES) scan was done using changing of dihedral angles N23-C13-C4-C5 (91), N23-N24-C26-O27 (92), N24-C26-C28-C29 (93, Fig. 1) from -180° to 180° with the step of 10°. Quantitative QTAIM (Quantum Theory of Atoms in Molecules) analysis was performed using AIMAll software package [15].
RESULTS AND DISCUSSION
The example of the pathway of the PLP residue rotation (91) is given (Fig. 2). Relative values of the dihedral N23-C13-C4-C5 in the transition states are close to (±)100°. The PLP moiety in the DU(-33) ground state could possibly freely oscillate in the range of dihedral values of (-20°^20°) since the energy required for these variation do not exceed 2.5 kJ mol-1 (kNAT, when T = 298.15 K).
AE, kJ/mol
30 л 2520151050-
UU(-32)
\
UU(-32)
\.DU(-33)/.
-160 -120 -80 -40 0
40 80 120 160
relative angle (N -C -C -C
0 v 23 13 3 4"
Fig. 2. Potential energy function of ф1 rotation in the PLP-INH3-hydrazone
Рис. 2. Функция потенциальной энергии вращения ф1 в гидразоне PLP-INH3-
10
AE, kJ/mol
Г\
"\DU(33)/
\DU(-33). DU(33)I
vV
\DU(-33),
V/
-160 -120 -80 -40 0
40 80 120 160
angle (N -C -C -C
ь ^ 24 26 28 29y'
Fig. 3. Potential energy function of ф3 rotation in the PLP-INH3-hydrazone
Рис. 3. Функция потенциальной энергии вращения ф3 в гидразоне PLP-INH3-
8
6
4
2
0
The rotation of pyridine residue of isoniazid (93) could occur via two different transition states. The lesser one (ca. 2.5 kJ mol-1) is characterized by relative angle of N24-C26-C28-C29 close to 0°; pyridine ring of INH moiety is almost perpendicular towards the rest of the hydrazone molecule in the another one (ca. 8.2 kJ mol-1). Therefore, the preferable pathway is through the planar transition state.
During the DU^DD and UU^UD (92) rotations, the search for the transition states is complicat-
ed. First, the inversion of partly sp3 hybridized N23 atom occurs. Another issue is the simultaneous 93 value alteration during scanning the 92 dihedral angle. Therefore, DU^DD and UU^UD processes pathways could probably include more than one transitions state.
The results of quantum chemical calculations including optimized geometries and total energies related towards the most stable structure are given (Fig. 4).
Fig. 4. Conformation equilibria of PLP-INH3- hydrazone. Energies of ground states (bold) and changes in total energies of activations of
the transfer between species (TS, italic) are related towards the most stable conformer Рис. 4. Конформационные равновесия гидразона PLP-INH3-. Энергии основных состояний (полужирный) и изменения полной энергии активации конформационных переходов (TS, курсив) приведены по отношению к наиболее устойчивому конформеру
Table
Key parameters of the different conformers of PLP-INH3- hydrazone
Parameter DU (-33) DU (33) UU (-32) UU (32) DD (-48) DD (42) UD
AE* (kJ mol-1) 0.19 0.00 11.40 11.41 8.20 9.81 17.19
AG* (kJ mol-1) 0.00 1.07 11.04 11.12 5.85 11.52 19.43
Bond lengths, Â
C4-C13 1.443 1.443 1.444 1.444 1.445 1.444 1.445
C13-N23 1.295 1.295 1.297 1.297 1.294 1.295 1.294
N23-N24 1.376 1.376 1.378 1.378 1.382 1.383 1.370
N24-C26 1.360 1.360 1.359 1.359 1.356 1.357 1.361
C26-O27 1.229 1.229 1.230 1.230 1.235 1.236 1.238
C26-C28 1.506 1.506 1.506 1.506 1.502 1.501 1.511
Dihedral angles,°
Ф1 -179.0 -179.5 -0.2 -0.7 170.3 172.3 0
ф2 179.0 -178.2 178.6 -178.3 -11.6 8.6 -180.0
фз -33.0 32.5 -32.2 32.3 -47.8 42.0 0
related towards the total or free energy of the most stable conformer
по отношению к полной либо свободной энергии наиболее устойчивого конформера
3
DU species (see Fig. 1 for naming principle) are the most stable among all possible ones. The molecule of DU form is non-planar due to the steric repulsion between hydrogens of pyridine ring of isoniazid residue (H34) and -NH- group (H25). Therefore, two stable structures are possible differing by 93 value; they are marked as DU(93) (See Fig. 4). These species are equal in energy; the geometry of the molecular fragment between two pyridine moieties is also the same (Table 1). Activation barrier of DU(-33)^DU(33) transition is low (AE = ~2.5 kJ/mol) allowing quick exchange.
Analogously, UU species are also capable of forming two structures with different 93 value. The rotation of the PLP residue around C3-C13 bond (conformational transition DU^UU) leads to the decreasing of the distance between methylene and -CH= group protons (4.0 A vs. 2.2 A) which could be responsible for the slightly increased total energy compared with DU structures. Geometry parameters of the hydrazone central fragment differ insignificantly in the DU and UU species (Table 1).
Activation barrier for the UU(-32)^UU(32) transition is similar to that of DU 93 rotation since both cases the molecule goes through the planar structure with the same distance between protons of pyri-dine residue and -NH- group (1.953 A).
In the DD species, pyridine ring of isoniazid residue is close to the methylene phosphate moiety of PLP fragment. It results in more strong steric repulsion and, thus, bigger non-planar distortion (|93|>40°). Besides, due to the fact that -CH2- group does not lie exactly within the same plane with pyridine residue of pyridoxal 5'-phosphate, the conformers differing by 93 value become non-equivalent energetically in relatively significant degree (AE 8.20 vs. 9.81; AG 5.85 vs. 11.52 kJ mol-1). It also increases the rotation barrier of the DD(-48)^DD(42) transition, since the angle C26-C28-C29 has to be increased in the transition state compared with ground states (~126.0 vs. ~123.0).
The DD species geometry of the central part of hydrazone molecules changes somewhat more significantly (Table 1, compare DU and UU vs. DU and DD).
Finally, UD structure is the least stable among all studied species and form no conformers due to 93 rotation. Though planar, it is not completely free from steric hindrance. The interaction between methylene and -CH= as well as -CH= and -NH- protons could probably increase its total and free energy (see Table 1). The shortening of the N23-N24 bond as well as the lengthening of the C26-C28 bond are notable changes in the geometry of hydrazone comparing with DU structures (Table 1). According AIM calculations the
charge q(H34) in UD structure is increased as compared with other conformers (UD>DD>UU«DU: +0.15^+0.07^ +0.05^+0.05). In case of UD conformer we found the bond critical points (BCPs) corresponding to hydrogen bonds N23 "^34 and O12--H34. The values of electron density p(r) in BCPs are 0.022 (N23-H34) and 0.010 (O12-H34) a.u. The values of Laplacian of electron density Vp(r) are 0.081 (N23-H34) and 0.033 (O12-H34) a.u. For hydrogen bonds values of p(r) and Vp(r) in BCP should lie in the range from 0.002 to 0.035 a.u. and from 0.024 to 0.139 a.u., respectively [16].
The transitions between ф1 and ф2 conformers could be concluded to occur relatively fast since the values of rotation barriers are low (20-30 kJ mol-1). The barriers of ф3 rotations do not exceed 10 kJ mol-1.
The analysis of conformational behavior of hydrazones is related to their coordination properties. The X-ray diffraction study of Cu(II) and Fe(III) complexes with pyridoxal isonicotinoyl hydrazone ans 2-hydroxy-1-naphtaldehyde isonicotinoyl hydrazone [7] have shown these ligands to be tridentate. They interact with metal ions through the oxygen atoms of carbonyl and hydroxyl groups as well as nitrogen of -CH=N- group. The complexes of ML and ML2 composition could be formed this way.
Therefore, all the groups coordinating the metal ion should be oriented 'up' in order to make the complex formation possible. Among the studied con-formers, the UU species are the only ones capable of metal binding. However, they are relatively unstable structures in the solution as it follows from the total energies calculations (Fig. 2). Thus, the PLP-INH3-hydrazone should exist predominantly as a mixture of DU species in the solution. There are the costs of the energy required for the DU^UU transition. Alteration of the aromatic substituents structure on either end of central chain (C13-N23-N24-C26) may reduce or increase the contribution of conformation change and, thus, influence the stability of metal-hydrazone complex.
The studies on the conformational behavior of the hydrazone relate also to its binding ability towards the protein molecule. The preliminary prediction of biological activity of PLP-INH hydrazone performed using PASS Online [17, 18] has shown it being the potential inhibitor of the G-protein-coupled receptor kinase (GRK) inhibitor with Pa = 0.975; Pi = 0.001 (Pa - probability of being active, Pi - probability of being inactive). This property of hydrazone is important since the inhibition of adrenergic receptors kinase is recognized by some authors as promising strategy of heart failure treatment [19]. The 4-pyridinyl hydrazone moiety is known to act by competitive inhibition of ATP, binding to the kinase active site [20].
In order to figure out, which conformation could probably exist in the complex with protein, we have performed docking using the optimized geometries of different conformers of hydrazone (as ligand) and crystal structure of GRK (as macromolecule) taken from [20] as input data. The scanning area was set to include the following amino acids residues, Phe202, Lys220, Asp335, and Met274 since they are the part of the kinase active site [20]. The AutoDock Vina software was used for docking [21].
The results are similar for all seven initial conformers. Each of them can form nine binding modes with the binding affinity varying within the range of (-32)^(-27) kJ mol-1. The calculated structure of the most stable complex is given (Fig. 5).
Fig. 5. Calculated structure of the complex of PLP-INH3" hydrazone
and active site of GRK2 Рис. 5. Расчетная структура комплекса гидразона PLP-INH3-и активного сайта GRK2
The hydrazone mode with the most binding affinity (Fig. 5) is close to the UU conformer. However, it is additionally twisted as it is follows from the dihedral angles values of this conformer (ф1 = 101.8°; ф2 = 25.4°; фз = -29.6°) when compared to those of UU (Table 1). The ligand could be also concluded to be too short to bind efficiently, since the distances between PLP-INH3- and Met274 and Phe202 are about 4 A. Probably, spacers insertion is in order.
CONCLUSIONS
The geometry of different conformers of the hydrazone derived from pyridoxal 5'-phosphate and isoniazid was optimized by means of quantum chemical calculations (DFT, B3LYP/6-311++G(d,p)). Con-formers differ one from another by the dihedral angles values of N23-C13-C4-C5, N23-N24-C26-O27 and N24-C26-C28-C29. Most of the studied species, except for UD structure, are non-planar due to the steric repulsion between hydrogen atoms of methylene, methyne or -NH- groups. The stability of conformers evaluated from their total energy values decreases in the following sequence: DU>DD(-48)> DD(42)>UU>UD.
The transitional states geometry referring to the ф1, ф2, фз rotation was optimized as well and the
values of activation barriers were estimated. The conformation equilibria are fast since the largest AG* does not exceed 30 kJ mol-1.
The most stable conformer is incapable of complexating the metal ions. The positive change in the total energy between it and the species forming the complex (namely, UU) contributes into the complexation thermodynamics.
The docking performed for PLP-INH3-hydrazone and G-protein-coupled receptor kinase revealed that the conformation of ligand bound to the active site is close to UU. However, it is additionally twisted in relation to the UU conformer, e.g. in terms of ф1 dihedral angle values (101.8° vs. ~0-1°).
Acknowledgements. The study was carried out in the Research Institute of Thermodynamics and Kinetics of Chemical Processes with financial support of Russian Foundation of Basic Research (project no. 16-33-60017) and Council on grants of the President of the Russian Federation (project no. 14.Z56.18.877-MK). We thank Prof. G. V. Girichev and Prof. A.V. Belyakov for their help in conducting the quantum chemical calculations on computing resources of the department of physics of Ivanovo State University of Chemistry and Technology and Saint Petersburg State Institute of Technology (Technical University).
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Поступила в редакцию 30.05.2018 Принята к опубликованию 05.10.2018
Received 30.05.2018 Accepted 05.10.2018
