In silico дослідження афінності зв’язування фенілзаміщенних 1,3-оксазолів з молекулами білків
The new model approach of interaction between the pharmacophores with bio-molecules, fragment-to-fragment, is presented. It is a new step of the molecular modeling and takes correctly into consideration not only the spatial complementarity of the interacted molecules but also the contribution of the...
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V.P. Kukhar Institute of Bioorganic Chemistry and Petrochemistry of the National Academy of Sciences of Ukraine
2020
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Ukrainica Bioorganica Acta| _version_ | 1871193577741090816 |
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| author | Zhuravlova, Maryna Yu. Obernikhina, Nataliya V. Pilyo, Stepan G. Kachaeva, Maryna V. Kachkovsky, Oleksiy D. Brovarets, Volodymyr S. |
| author_facet | Zhuravlova, Maryna Yu. Obernikhina, Nataliya V. Pilyo, Stepan G. Kachaeva, Maryna V. Kachkovsky, Oleksiy D. Brovarets, Volodymyr S. |
| author_institution_txt_mv | [
{
"author": "Maryna Yu. Zhuravlova",
"institution": "National University of \"Kyiv-Mohyla Academy\", 2 Skovoroda St., Kyiv, 04070, Ukraine"
},
{
"author": "Nataliya V. Obernikhina",
"institution": "O.O. Bogomolets National Medical University, 13 Shevchenko Blvd., Kyiv, 01601, Ukraine"
},
{
"author": "Stepan G. Pilyo",
"institution": "V.P. Kukhar Institute of Bioorganic Chemistry and Petrochemistry of the NAS of Ukraine, 1 Murmanska St., Kyiv, 02094, Ukraine"
},
{
"author": "Maryna V. Kachaeva",
"institution": "V.P. Kukhar Institute of Bioorganic Chemistry and Petrochemistry of the NAS of Ukraine, 1 Murmanska St., Kyiv, 02094, Ukraine"
},
{
"author": "Oleksiy D. Kachkovsky",
"institution": "V.P. Kukhar Institute of Bioorganic Chemistry and Petrochemistry of the NAS of Ukraine, 1 Murmanska St., Kyiv, 02094, Ukraine"
},
{
"author": "Volodymyr S. Brovarets",
"institution": "V.P. Kukhar Institute of Bioorganic Chemistry and Petrochemistry of the NAS of Ukraine, 1 Murmanska St., Kyiv, 02094, Ukraine"
}
] |
| author_sort | Zhuravlova, Maryna Yu. |
| baseUrl_str | https://bioorganica.com.ua/index.php/journal/oai |
| collection | OJS |
| datestamp_date | 2026-07-19T14:56:52Z |
| description | The new model approach of interaction between the pharmacophores with bio-molecules, fragment-to-fragment, is presented. It is a new step of the molecular modeling and takes correctly into consideration not only the spatial complementarity of the interacted molecules but also the contribution of the stacking p-p-electron interaction and hydrogen bonds. As an example, the correct analysis of the interaction of the biological active phenyl-substituted 1,3-oxazoles with protein fragments is performed. It was shown that the length and energy of the hydrogen bond uniquely depend on the chemical constitution of both components in the created complex [Pharmacophore(Oxazole)-Biomolecule (H-X)]. The binding energy regularly decreases in the series X → O, S, NH (fragments of the corresponding biomolecules). It should be pointed out that introduction of the conjugated phenyl groups at positions 2 and 5 of oxazoles increase the stability of the possibly generated complex Pharmacophore-Biomolecule [Pharm-BioM] with fragments of the corresponding biomolecules along the core of oxazole by 0.2 and 0.5 kcal/mole. At the same time, modeling of the possibly generated complex [Pharm-BioM] by phenyl substituents at position 2 and 5 of 1,3-oxazole with phenylalanine as a fragment of protein molecules additionally stabilizes complex by 2.5 kcal/mole by p-stacking mechanism. It seems, the observed biological activity of the phenyl substituted 1,3-oxazole is rather connected with the possibility to generate the stable complex due to the formation of additional bonds with other fragments (conjugated phenyl core). The calculations give that such substituents do not cause spatial hindrances with the polypeptide chain. |
| doi_str_mv | 10.15407/bioorganica2020.01.012 |
| first_indexed | 2025-07-17T12:19:34Z |
| format | Article |
| fulltext |
ISSN 1814-9758. Ukr. Bioorg. Acta, 2020, Vol. 15, N 1
UDC 544.182.32+547.31.39+547.787.1+547.874.8
DOI: https://doi.org/10.15407/bioorganica2020.01.012
12
RESEARCH ARTICLE
In silico binding affinity studies of phenyl-substituted 1,3-oxazoles with
protein molecules
Maryna Yu. Zhuravlova1, Nataliya V. Obernikhina2*, Stepan G. Pilyo3, Maryna V. Kachaeva3,
Oleksiy D. Kachkovsky3, Volodymyr S. Brovarets3
1National University of "Kyiv-Mohyla Academy", 2 Skovoroda St., Kyiv, 04070, Ukraine
2O. O. Bogomolets National Medical University, 13 Shevchenko Blvd., Kyiv, 01601, Ukraine
3V. P. Kukhar Institute of Bioorganic Chemistry and Petrochemistry of the NAS of Ukraine, 1 Murmanska St., Kyiv, 02094, Ukraine
Abstract: The new model approach of interaction between the pharmacophores with bio-molecules, fragment-to-fragment, is presented. It
is a new step of the molecular modeling that takes correctly into consideration not only the spatial complementarity of the interacted
molecules but also the contribution of the stacking --electron interaction and hydrogen bonds. As an example, the correct analysis of the
interaction of the biological active phenyl-substituted 1,3-oxazoles with protein fragments is performed. It was shown that the length and
energy of the hydrogen bond uniquely depend on the chemical constitution of both components in the created complex
[Pharmacophore(Oxazole)-Biomolecule (H-X)]. The binding energy decreases in the series X → O, S, NH (fragments of the
corresponding biomolecules). It should be pointed out that introduction of the conjugated phenyl groups at positions 2 and 5 of oxazoles
increase the stability of the generated complex Pharmacophore-Biomolecule [Pharm-BioM] with fragments of the corresponding
biomolecules along the core of oxazole by 0.2 and 0.5 kcal/mole. At the same time, modeling of the generated complex [Pharm-BioM] by
phenyl substituents at position 2 and 5 of 1,3-oxazole with phenylalanine as a fragment of protein molecules additionally stabilizes
complex by 2.5 kcal/mole by -stacking mechanism. The observed biological activity of the phenyl substituted
1,3-oxazole is rather connected with ability to generate the stable complex due to the formation of additional bonds with other fragments
(conjugated phenyl core). The calculations demonstrated that such substituents do not cause spatial hindrances with the polypeptide chain.
Keywords: biological affinity, 1,3-oxazoles, quantum chemical calculations, [Pharm-BioM] complex, -stacking interaction, hydrogen
bonds.
Introduction
The oxazole-based five-membered heterocycles exhibit
various pharmacologically interesting properties that have
recently been reported in several reviews [1-2]. It enabled
the wide introduction of novel pharmacological drugs into
medicine. The 1,3-oxazoles with branched conjugated
systems demonstrated high biological activity, including
antibacterial and antiviral activities [3-4], and multiple drug
resistance pump inhibition [5-6]. The substituted
Received:
Revised:
Accepted:
Published online:
20.03.2020
03.04.2020
10.04.2020
30.06.2020
Corresponding author. Tel.: +380-96-225-7764;
e-mail: nataliya.obernikhina@nmu.ua (N. V .Obernikhina)
ORCID: 0000-0003-1143-8924
1,3-oxazoles with branched -conjugated systems also were
studied in vitro at the National Cancer Institute in the USA,
as part of a therapeutic program for the development of
DTP. It was found that these compounds are promising
component in the development of new biologically active
substances exhibiting antitumor activity which is strongly
dependent on the nature of the substituents in heterocyclic
core [7-10]. That leads to additional research activity
toward developing new pharmaceuticals [11-12].
The QSAR models for a wide range of 1,3-oxazole
derivatives showed an inhibitory effect on several cancer
cell lines. A good correlation between many descriptors and
biological activity was established [8]. Therefore, the planar
oxazole core can be regarded as an applicable biologically
active fragment. Its lone electron pair (LEP) at the two-
coordinated nitrogen atom can promote the additional
stabilization of [Pharm-BioM] complex by hydrogen bonds.
© Zhuravlova M. Yu. et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits
unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
Ukrainica Bioorganica Acta
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ISSN 1814-9758. Ukr. Bioorg. Acta, 2020, Vol. 15, N 1
13
At the same time, the introduction of substituents with a
conjugated -electron system in the 1,3-oxazole ring
increases the stabilization of resulted complex [Pharm-
BioM] by -stacking interaction. The presence of the phenyl
substituent in 1,3-oxazole substrate increases biological
activity, particularly, the inhibitory effect on the cancerous
tumors [9-10]. These molecular fragments can generate an
additional complementary structure with many
biopolymers, which is considered an important condition
for increasing selectivity for potential targets.
This paper presents the results of the in silico
investigations of the connection between biological
properties and electronic structure of phenyl substituted
1,3-oxazoles, including the steric features as well as
additional stabilization of the model [Pharm-BioM]
complex by stacking interaction and by generation
hydrogen bonds.
Materials
The 4-cyano substituted 1,3-oxazole derivatives were
investigated (Figure 1) as biologically active compounds for
interaction with protein fragments. Typically, electron
accepting groups at the 4th position of 1,3-oxazoles increase
the stability of the 5-membered electron-rich oxazole cycle.
Moreover, oxazole derivatives containing similar
substituents have demonstrated high biological activity [9].
N
O
R(5)
CN
R(2)
Compd R(2) R(5)
1 Me Me
2 Ph Me
3 Me Ph
4 Ph Ph
Figure 1. Structures of compounds 1-4.
The dimethyl substituted oxazole 1 was chosen as a
reference molecule; the one- and two-phenyl substituted
derivatives 2-4 were compared to oxazole 1. Compounds
1-4 were evaluated at the National Cancer Institute (NCI)
for anticancer activity in vitro. Primary in vitro one dose
anticancer assay was performed in full NCI 60 cell panel
representing leukemia, melanoma, and cancers of lung,
colon, brain, breast, ovary, kidney, and prostate in
accordance with the protocol of the NCI, USA [9].
The main characteristics of the electron structure
(optimized molecular geometry, charge distribution,
energies and shapes of molecular orbitals) were calculated
by DFT computation utilizing wB97XD function and
6-31G(d,p) basis set as implemented in GAUSSIAN 03
program [13].
Binding affinity by fragment-to-fragment approach
Typically, the biological affinity of pharmacophores
evaluated by their ability to effectively interact with
biological molecules. The pharmacophore (Pharm) and bio-
molecule (BioM) should form a stable complex, namely
[Pharm-BioM]. The stability of such complex depends on
the geometrical characteristics of both complex
components. The complex can be additionally stabilized by
creating hydrogen bonds and stacking interactions with
phenyl substituents. The oxazole and its conjugated
substituted derivatives are planar molecules and, hence,
should be attracted to protein fragments. The amino acids
with the aromatic groups as part of its structural
characteristics can create a -complex [Pharm-BioM] with
oxazole derivatives 1-5. Therefore the ability to form the
-complex can be considered as a -electron affinity
component. Similarly, the ability to form a complex by
hydrogen bonds can be considered as an [H-B] affinity
component. As a result, the oxazole -electron cycle can
manifest the -affinity whereas the two-coordinated
nitrogen atom of the oxazole ring can manifest its [H-B]-
affinity. These properties can be evaluated by a direct
quantum-chemical modeling.
Many events of the [Pharm-BioM] interactions can be
modeled by elementary interactions between the
pharmacophore fragments (1,3-oxazoles) and some
fragments of the complex biological molecules by taking
into consideration the complementarity of the complex
components. We will call this approach a fragment-to-
fragment approach.
Results and Discussion
Molecular geometry of substituted 1,3-oxazoles and
charge distribution
The 1,3-oxazoles are conjugated planar molecules. The
optimization of the molecular geometry of phenyl
substituted oxazoles 2-4 with variable substituents in
positions 2 and 5 confirmed planar configuration.
According to the complementarity rule such compounds
should predominantly form complexes [Pharm-BioM] with
protein fragments that contain conjugated aromatic amino
acids (phenylalanine, tyrosine, tryptophan, histidine). These
complexes are additionally stabilized by stacking
interaction between -electron systems of both complex
components.
Earlier, we have demonstrated that the binding energy of
the complex [Pharm-Fullerene] depends on the nature of the
substituent in the oxazole ring [14]. We hypothesized that
the binding energy of complex [Pharm-BioM] formation
depends on the nature of the substituent at the 2- and
5-positions of 1,3-oxazoles 1-4. This dependence should be
similar for all types of donor/acceptor characteristics of
these biomolecules. The complex formation of 1,3-oxazole
M. Yu. Zhuravlova, N. V. Obernikhina, S. G. Pilyo et al.
14
Figure 2. Optimized molecular geometry of three possible complexes of 1,3-oxazole 4 with a model phenylalanine (toluene): a) -stacking
by phenyl group at position 2; b) -stacking by phenyl group at position 5; v) -stacking by 1,3-oxazole cycle.
4 with phenylalanine [oxazole-Phe] was examined.
Phenylalanine in a polypeptide chain was modeled by
toluene, i.e. only conjugated system was taken into
consideration. The geometrical characteristics of phenyl
group of toluene is similar to the fragments of the phenyl-
substituted 1,3-oxazole 4. As a result, we calculated
different possible versions of the generated complex:
(i) when the central heterocycle is oriented to model
phenylalanine or (ii) when one of the phenyl-group of
oxazole 4 is oriented toward model phenylalanine. Three
possible complexes of diphenyl substituted oxazole with
toluene are presented in Figure 2.
It is noteworthy that the thickness of -electron systems
is 3.4 Å, the distance between the components in the studied
complex [Pharm-BioM] (i.e., between 1,3-oxazole cycle,
phenyl substitutes in the 2- and 5-positions of 1,3-oxazole 4
and model phenylalanine – toluene) is 3.4 Å. Similar
founding was reported for deoxyribonucleic acid helix [16]
and for polymethine dyes aggregates [17].
Positions of the frontier orbitals of compounds 1-4 and
its donor/acceptor properties
We assumed that biological activity is connected to the
position of frontier orbitals as it was reported previously
[15]. The oxazole ligand produces complex with peptide
fragments by protein-ligand complex binding [Pharm-
BioM] [18]. These results indicates the stacking interaction
between the -systems of both complex components: A
(Pharmacophore) and B (Biomolecule). According to the
perturbation theory [19], a similar interaction depends on
the relative positions of the molecular orbitals of both
molecules as well as the overlapping of their -systems and
can be calculated by Equation 1:
(1)
(
where i and j are MO energies; Ci and Cj are MO
coefficients; indіces i, is energy system A; indіces j, is
energy system B.
The main contributions to the frontier molecular orbitals
(MO) are made by the highest occupied MO (HOMO) and
the lowest unoccupied MO (LUMO). The geometry of the
frontier molecular orbitals contribute to the donor and
acceptor ability of the conjugated molecules. The influence
of the phenyl groups on the energy level of both HOMO
and LUMO are presented in Table 1.
а
b
c
E
A A
i
B B
j ji
ji CC
ISSN 1814-9758. Ukr. Bioorg. Acta, 2020, Vol. 15, N 1
15
Table 1. Energies of frontier MO of substituted
1,3-oxazoles 1-4.
Compd
R(2) R(5) (MO), eV ,
eV
0
a
HOMO LUMO
1 Me Me -8.822 1.137 9.958 0.472
2 Ph Me -8.307 0.386 8.694 0.454
3 Me Ph -8.228 0.049 8.277 0.436
4 Ph Ph -8.004 -0.173 7.830 0.433
a 0 calculated by Equation 2.
The introduction of the phenyl groups in position 2 or 5
of oxazole ring are accompanied by converging of the
frontier orbitals so that energy gap (difference between the
energy of highest occupied orbital and lowest vacant
orbital) decreases. Phenyl group in position 5 causes the
greater effect (1.68 eV) compared to the phenyl substituent
in position 2 (1.26 eV). There is no additive effect found
upon simultaneous introduction of two phenyl groups to
positions 2 and 5 (2.12 eV).
It was proposed [20] to calculate the donor/acceptor
ability of the molecules as a relative position of the frontier
orbitals by the following Equation 2:
0 = (LUMO - (F)/( (LUMO - (HOMO) (2)
Where LUMO is an energy of the lowest unoccupied MO,
HOMO is an energy of the highest occupied MO, F () is an
energy of non-bonding MO ( = -3.561 eV) [21].
The calculated values 0 for studied compounds are
presented in Table 1. The data shows that this parameter is
slightly sensitive to introduction of phenyl groups. The
phenyl substituent generates the equal number of occupied
and unoccupied MO, which symmetrically positioned from
the non-bonding MO (Fermi level ) [21]. The acceptor
property (0 < 0.5) is caused by cyano group (-CN) in
position 4, although the oxazole per se is molecule with
donor properties as an electron rich system [18].
Binding energies of -complex [Pharm-BioM]
In the first approximation, the binding energy Ebinding can
be calculated as the difference of the total energy of the
complex [Pharm-BioM] and the energies of both its
components (Eq. 3):
Ebinding = E[Pharm-BioM] – EPharm – EBioM (3)
where E[Pharm-BioM] is the energy of optimized complex,
while EPharm and EBioM are energies of optimized
components.
This work focuses on the protein fragment in the form of
model phenylalanine (Phe-CH3), which can create a
-complex. The calculations of the donor/acceptor
parameter 0 of the phenylalanine amino acid gives
0 = 0.52; while this parameter of the model fragment,
Phe-CH3, is equal to 0 = 0.53. We are investigating the
influence of the phenyl substitution in positions 2 and 5 that
resulted in change of a -contribution as well as total
affinity of the oxazoles 1-4 in a model complex
[Oxazole:Phe-CH3].
Figure 2 depicted three possible geometries of both
components in the model complex. The optimization
showed that the distance between components in the stable
complex is approximately 3.4 Å. The calculated binding
energies of the optimized complexes [Oxazole:Phe-CH3]
are presented in Table 2.
As it can be seen (Table 2 and Figure 2c) that one phenyl
group (compounds 2 and 3) increases the complex stability
by orienting the phenyl group to the heterocyclic fragment;
in the complex that is formed from di-phenyl-substituted
1,3-oxazole 4, the binding energy is less than in the
complex with the reference molecule 1.
The stabilization energy of the complex 2c
[Oxazole:Phe-CH3] is significantly lower compared to other
complexes’ geometries (Figure 2, Table 2). It is noteworthy
that the stabilization energy of the complex that is formed
from two phenyl substituted oxazole is minimum among all
possible complexes. However, the preferential formation of
Table 2. Binding energies of complexes [Oxazole:Phe-CH3], where oxazole corresponds to compounds 1-4.
Figure Complex
R(2) R(5) Energy (E)a, a.u. Eb,
kcal/mole
Oxazole Complex
2c [Oxazole 1:Phe-CH3] Me Me -416.825544294 -688.327544051 -12.18
2c [Oxazole 2:Phe-CH3] Ph Me -608.502926733 -880.005254882 -12.38
2a [Oxazole 2:Phe-CH3] Ph Me -880.002988419 -10.96
2c [Oxazole 3:Phe-CH3] Me Ph -608.502469135 -880.005254882 -12.67
2b [Oxazole 3:Phe-CH3] Me Ph -880.000764847 -9.85
2c [Oxazole 4:Phe-CH3] Ph Ph -800.180950747 -1071.68207547 -11.63
2a [Oxazole 4:Phe-CH3] Ph Ph -1071.67606230 -7.86
2b [Oxazole 4:Phe-CH3] Ph Ph -1071.67528637 -7.37
Phe-CH3 -271.482591603
aE is total energy.
bE is binding energy increases only the stability of the formed complex.
M. Yu. Zhuravlova, N. V. Obernikhina, S. G. Pilyo et al.
16
various complexes with the orientation at the heterocycle
(Figure 2c) will be difficult because of spatial hindrances
with the polypeptide chain.
The formation of hydrogen bonding in [H-B] complex
The oxazole cycle contains a coordinated nitrogen atom
(with the lone electron pair – LEP) in position 3. It can be
considered as an acceptor center for the formation of
hydrogen bonds, while the hydrogen atom of the amino
group of some acids (lysine, arginine, histidine, etc.) or
groups containing hydrogen (-NH, -OH and -SH) can
provide the required proton, i.e. the hydrogen bonds can be
formed during complex’s formation. This interaction should
result in the additional stabilization energy of complexes
[Oxazole:H-X] that are formed between oxazole molecules
and suitable fragments of biomolecules, where X is a N, O,
S atoms.
In our study, the donor centers were modeled by the
simplest molecules: methanol HO-CH3, methylamine
H2N-CH3 and methanethiol HS-CH3. Possible complexes of
the model bio-fragments with the 1,3-oxazoles 1-4 are
shown in Figure 3.
The model peptide fragment and oxazole cycle are
positioned perpendicularly. Moreover, the formation of
hydrogen bond should depends on the charge at the nitrogen
atom as well as on the relative position of the LEP (n-MO).
Calculation revealed that the n-MO is localized near the
nitrogen atom, and it actively interacts with the -orbital, as
it presented in Figure 4. n-MO is located directly below of
the frontier orbitals: HOMO-1. In the case of phenyl
derivatives, the local orbital (MOs localized only on phenyl
molecular fragment) are situated between the delocalized
HOMO and the n-MO. Nevertheless, the energy level of
n-MOs remains practically the same after every change in
the reference oxazole cycle. The calculated atomic charges
and n-MO energies are presented in Table 3.
Table 3. Charge at nitrogen atom (z) and n-MO energy ()
of substituted oxazoles 1-4.
Compd R(2) R(5) z, e.u. n-MO
number , eV
1 Me Me -0.457 HOMO-1 -10.63
2 Ph Me -0.454 HOMO-3 -10.69
3 Me Ph -0.491 HOMO-3 -10.70
4 Ph Ph -0.458 HOMO-5 -10.77
Table 3 shows that introducing of phenyl group in
position 2 slightly decreases a negative charge at the
nitrogen atom whereas the phenyl in position 5 causes the
opposite effect.
The energy of three complexes of the reference molecule
1 with three model compounds H-X-CH3 where X is a N, O,
S atoms as well as three complexes of one model bio-
fragment, H2N-CH3, with substituted 1,3-oxazoles 2-4 were
calculated and presented in Table 4.
It was found that the length of the hydrogen bond and the
binding energy depends on the chemical structure of both
components in the generated [Oxazole:H-X] complex.
Thus, the change of heteroatoms in a model bio-fragment
[H-B(X)] decreases the binding energy and, therefore, the
stabilization of the corresponding complex in series: X →
O, S, NH. The length of a hydrogen bond is shorter during
the interaction with –OH group, whereas the lengths of a
hydrogen bond with –NH2 and –SH groups are essentially
the same.
The introduction of the phenyl substituents does not
change the length of hydrogen bonds in the corresponding
complex: lN
-…H 2.01 0.01 Å. Moreover, the binding
energy is considerably more sensitive to position of the
introduced phenyl groups as well as to the number of
Figure 3. Calculated geometry of 1,3-oxazole molecule 1-4 and model fragments of biomolecules: a) methanol; b) methanethiol;
c) methylamine.
a b c
ISSN 1814-9758. Ukr. Bioorg. Acta, 2020, Vol. 15, N 1
17
Figure 4. Position and shape of frontier and nearest MOs in 1,3-oxazoles 1-4.
Table 4. Hydrogen bond energy of complex [Oxazole:H-X] with model methanol, methylamine, and methanethiol.
Complex
R(2) R(5) X lN-…H
a,
Å
Energy (E), a.u. Ebinding
b,
kcal/mole
Oxazole Complex
[Oxazole 1:H-X] Me Me -O 1.838 -416.82554429 -532.52885310 -11.47
[Oxazole 1:H-X] Me Me -HN 2.252 -416.82554429 -512.66886008 -7.68
[Oxazole 1:H-X] Me Me -S 2.232 -416.82554429 -855.50852371 -9.11
[Oxazole 2:H-X] Ph Me -O 1.989 -608.50292673 -724.20719212 -12.08
[Oxazole 3:H-X] Me Ph -O 2.018 -608.50246913 -724.20876140 -13.34
[Oxazole 4:H-X] Ph Ph -O 1.996 -800.18095074 -915.88462187 -11.70
H-O-CH3 -115.68502789
H-HN-CH3 -95.831078854
H-S-CH3 -438.66846361
alN-…H is hydrogen bond length.
bEbinding is binding energy.
-12
-10
-8
-6
-4
-2
0
2
4
E, eV
LUMO
L0
L(+1)
L(+2)
HOMO
H 0
H(-1)
H0
H(-3)
H0 H0
H(-3) H(-5)
L0 L0
L0
N
O
CH3
CN
H3C
N
O
Ph
CN
H3C
N
O
CH3
CN
Ph
N
O
Ph
CN
Ph
1 3 2 4
1
1
Zhuravlova M. Yu., Obernikhina N.V., Pilyo S. G. et al.
18
Table 5. Anticancer activity of synthesized compounds [22] model 1,3-oxazoles 2-4, and their theoretical characteristics.
Compd R(2) R(5)
0
-stack
interaction
H-bond
interaction
Anti-Cancer Activity [22], %
E, kcal/mol
Leukemia
(RPMI-8226)
Non-Small Cell
Lung Cancer
(EKVX)
1 Me Me 0.472 -12.18 -9.11 - -
2 Ph Me 0.454 -12.4a/10.9b -12.08 99.2 73.1
3 Me Ph 0.436 -12.7a/9.9c -13.34 79.3 94.3
4 Ph Ph 0.433 -11.6a/-7.9b/-7.4c -11.70 75.0 85.3
a-stack interaction according to Figure 2с. b-stack interaction according to Figure 2a. c-stack interaction according to Figure b.
substituents. The maximum stabilization energy of complex
[Oxazole:H-X] (Table 4) reached when the 1,3-oxazole
contains phenyl group in position 2 (compound 2). The
introduction of second phenyl group (compound 4)
decreases binding energy so that two phenyl substituents in
positions 2 and 5 do not change the stability of the
[Oxazole:H-X] complex, in compare with the reference
molecule 1 (R1 = R2 = CH3).
The tendenсy of the quantum-chemical approaches
and the anticancer activity of oxazole derivatives 1-4.
The synthesized compounds 1-4 were screened for
anticancer activity in the 60 cell panel in accordance with
the protocol of the NCI, USA, under the Developmental
Therapeutic Program DTP [22]. Table 5 presents data from
anticancer activity of synthesized compounds [9, 22] and
their theoretical characteristics from quantum-chemical
model fragment-to-fragment approach.
As can be seen from Table 5, the oxazole derivatives 2-4
inhibits of cell line EKVX (Non-Small Cell Lung Cancer)
growth due to the formation of hydrogen bonds and stable
[Pharm-BioM] complexes with regulatory proteins, which
on the outer sphere have free residues of proton donor
amino acids.
The growth’s inhibition of cell line RPMI-8226
(Leukemia) happened due to the interaction with regulatory
proteins that occurs by -stack interaction of oxazole
derivatives 2-4 with regulatory proteins that have open
aromatic amino acid residues.
Conclusions
The theoretical analysis of the interaction of biologically
active phenyl-substituted 1,3-oxazoles in the framework of
the fragment-to-fragment approach (beside the spatial
complementarity of the interacted molecules, the
contribution of the stacking --electron interaction and
hydrogen bonds is taken into consideration) reviled that
introduction of conjugated phenyl groups into main
heterocyclic platform will not increase the stability of
generated complexes. The observed biological activity of
substituted 1,3-oxazoles 2-4 can be explained by the
formation of additional bonds with other fragments
(conjugated phenyl core) during complex formation, so as
they do not cause the stearic hindrances with the
polypeptide chain.
Notes
The authors declare no conflict of interest.
Author contributions. M. Yu. Zh.: provision of study
materials, computing resources, or other analysis tools.
N. V. O.: formulation or evolution of overarching research
goals and aims, application of statistical, mathematical,
computational, or other formal techniques to analyze study
data. S. G. P.: development and design of methodology;
creation of models, provision of study materials, computing
resources, or other analysis tools. M. V. K.: preparation,
creation and presentation of the published work, specifically
visualization. O. D. K.: ideas; formulation or evolution of
overarching research goals and aims, development or design
of methodology; creation of models. V. S. B. ideas;
formulation or development of common goals and
objectives of the research, verification of results,
responsibility for managing and coordinating the planning
and implementation of research activities.
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In silico дослідження афінності зв’язування фенілзаміщенних 1,3-оксазолів з
молекулами білків
М. Ю. Журавльова1, Н. В. Оберніхіна2*, С. Г. Пільо3, М. В. Качаєва3, О. Д. Качковський3, В. С. Броварець3
1Національний університет "Києво-Могилянська академія", вул. Г. Сковороди, 2, Київ, 04070, Україна.
2Національний медичний університет імені О. О. Богомольця, бульв. Т. Шевченка, 13, Київ, 01601, Україна.
3Інститут біоорганічної хімії та нафтохімії ім. В. П. Кухаря НАН України, вул. Мурманська, 1, Київ, 02094, Україна.
Резюме: Представлений новий пофрагментний підхід моделювання взаємодії фармакофорів з біомолекулами. Це новий, наступний крок
молекулярного моделювання, який враховує не тільки просторову відповідну комплементарність взаємодіючих молекул, але й внесок
-електронів при стекінговій взаємодії та n-електронів при формуванні водневих зв’язків. Як приклад, проведено повний аналіз взаємодії
біологічно активних феніл-заміщених 1,3-оксазолів з білковими молекулами. Було показано, що довжина та енергія водневого зв’язку
однозначно залежать від хімічної конституції обох компонентів в утвореному комплексі [Фармакофор(оксазол)-Біомолекула(H-X)]. Енергія
зв’язку регулярно зменшується у ряді X → O, S, NH (фрагменти відповідних біомолекул). Введення спряжених фенільних груп в положення 2 та
5 оксазолу збільшує стабільність згенерованого комплексу Фармакофор-Біомолекула [Фарм-БіоM] з фрагментами відповідних біомолекул по
ядру оксазола на 0.2 ккал/моль та 0.5 ккал/моль. При моделюванні утворення комплексу [Фарм-БіоM] по фенільних замісниках 1,3-оксазолу в
положенні 2 та 5 з фенілаланіном як фрагментом білкових молекул спостерігається додаткова його стабілізація на 2.5 ккал/моль за механізмом
-стекінгової взаємодії. Скоріш за все, біологічна активність феніл- заміщених 1,3-оксазолів, яка спостерігається, пов'язана з можливістю
генерувати стійкий комплекс [Фарм-БіоM] за рахунок утворення додаткових -зв'язків з іншими фрагментами, що мають кон'юговане ядро.
Розрахунки показують, що такі замісники не викликають просторових утруднень з поліпептидними молекулами.
Ключові слова: біологічна афінність, 1,3-оксазоли, квантово-хімічні розрахунки, комплекс [Фарм-БіоМ], -стекінгова взаємодія, водневі зв’язки.
https://onlinelibrary.wiley.com/action/doSearch?ContribAuthorStored=Kachaeva%2C+Maryna+V
https://onlinelibrary.wiley.com/action/doSearch?ContribAuthorStored=Hodyna%2C+Diana+M
https://onlinelibrary.wiley.com/action/doSearch?ContribAuthorStored=Obernikhina%2C+Nataliya+V
https://onlinelibrary.wiley.com/action/doSearch?ContribAuthorStored=Pilyo%2C+Stepan+G
https://onlinelibrary.wiley.com/action/doSearch?ContribAuthorStored=Kovalenko%2C+Yulia+S
https://onlinelibrary.wiley.com/action/doSearch?ContribAuthorStored=Prokopenko%2C+Volodymyr+M
https://onlinelibrary.wiley.com/action/doSearch?ContribAuthorStored=Kachkovsky%2C+Oleksiy+D
https://onlinelibrary.wiley.com/action/doSearch?ContribAuthorStored=Brovarets%2C+Volodymyr+S
https://www.sciencedirect.com/science/article/pii/S1476927118301038
https://www.sciencedirect.com/science/article/pii/S1476927118301038
|
| id | oai:ojs2.bioorganica.com.ua:article-3 |
| institution | Ukrainica Bioorganica Acta |
| keywords_txt_mv | keywords |
| language | English |
| last_indexed | 2026-07-20T01:00:56Z |
| publishDate | 2020 |
| publisher | V.P. Kukhar Institute of Bioorganic Chemistry and Petrochemistry of the National Academy of Sciences of Ukraine |
| record_format | ojs |
| resource_txt_mv | bioorganicacomua/38/65a2b8ad91cf315786d67f91e7960438.pdf |
| spelling | oai:ojs2.bioorganica.com.ua:article-32026-07-19T14:56:52Z In silico binding affinity studies of phenyl-substituted 1,3-oxazoles with protein molecules In silico дослідження афінності зв’язування фенілзаміщенних 1,3-оксазолів з молекулами білків Zhuravlova, Maryna Yu. Obernikhina, Nataliya V. Pilyo, Stepan G. Kachaeva, Maryna V. Kachkovsky, Oleksiy D. Brovarets, Volodymyr S. biological affinity 1,3-oxazoles quantum chemical calculations [Pharm-BioM] complex p-stacking interaction hydrogen bonds біологічна афінність 1,3-оксазоли квантово-хімічні розрахунки комплекс [Фарм-БіоМ] п-стекінгова взаємодія водневі зв’язки The new model approach of interaction between the pharmacophores with bio-molecules, fragment-to-fragment, is presented. It is a new step of the molecular modeling and takes correctly into consideration not only the spatial complementarity of the interacted molecules but also the contribution of the stacking p-p-electron interaction and hydrogen bonds. As an example, the correct analysis of the interaction of the biological active phenyl-substituted 1,3-oxazoles with protein fragments is performed. It was shown that the length and energy of the hydrogen bond uniquely depend on the chemical constitution of both components in the created complex [Pharmacophore(Oxazole)-Biomolecule (H-X)]. The binding energy regularly decreases in the series X → O, S, NH (fragments of the corresponding biomolecules). It should be pointed out that introduction of the conjugated phenyl groups at positions 2 and 5 of oxazoles increase the stability of the possibly generated complex Pharmacophore-Biomolecule [Pharm-BioM] with fragments of the corresponding biomolecules along the core of oxazole by 0.2 and 0.5 kcal/mole. At the same time, modeling of the possibly generated complex [Pharm-BioM] by phenyl substituents at position 2 and 5 of 1,3-oxazole with phenylalanine as a fragment of protein molecules additionally stabilizes complex by 2.5 kcal/mole by p-stacking mechanism. It seems, the observed biological activity of the phenyl substituted 1,3-oxazole is rather connected with the possibility to generate the stable complex due to the formation of additional bonds with other fragments (conjugated phenyl core). The calculations give that such substituents do not cause spatial hindrances with the polypeptide chain. Представлений новий пофрагментний підхід моделювання взаємодії фармакофорів з біомолекулами. Це новий, наступний крок молекулярного моделювання, який враховує не тільки просторову відповідну комплементарність взаємодіючих молекул, але й внесок p-електронів при стекінговій взаємодії та n-електронів при формуванні водневих зв’язків. Як приклад, проведено повний аналіз взаємодії біологічно активних феніл-заміщених 1,3-оксазолів з білковими молекулами. Було показано, що довжина та енергія водневого зв’язку однозначно залежать від хімічної конституції обох компонентів в утвореному комплексі [Фармакофор(оксазол)-Біомолекула(H-X)]. Енергія зв’язку регулярно зменшується у ряді X → O, S, NH (фрагменти відповідних біомолекул). Введення спряжених фенільних груп в положення 2 та 5 оксазолу збільшує стабільність згенерованого комплексу Фармакофор-Біомолекула [Фарм-БіоM] з фрагментами відповідних біомолекул по ядру оксазола на 0.2 ккал/моль та 0.5 ккал/моль. При моделюванні утворення комплексу [Фарм-БіоM] по фенільних замісниках 1,3-оксазолу в положенні 2 та 5 з фенілаланіном як фрагментом білкових молекул спостерігається додаткова його стабілізація на 2.5 ккал/моль за механізмом p-стекінгової взаємодії. Скоріш за все, біологічна активність феніл- заміщених 1,3-оксазолів, яка спостерігається, пов'язана з можливістю генерувати стійкий комплекс [Фарм-БіоM] за рахунок утворення додаткових p-зв'язків з іншими фрагментами, що мають кон'юговане ядро. Розрахунки показують, що такі замісники не викликають просторових утруднень з поліпептидними молекулами V.P. Kukhar Institute of Bioorganic Chemistry and Petrochemistry of the National Academy of Sciences of Ukraine 2020-06-30 Article Article application/pdf https://bioorganica.com.ua/index.php/journal/article/view/3 10.15407/bioorganica2020.01.012 Ukrainica Bioorganica Acta; Vol. 15 No. 1 (2020): Ukrainica Bioorganica Acta; 12-19 Ukrainica Bioorganica Acta; Том 15 № 1 (2020): Ukrainica Bioorganica Acta; 12-19 1814-9766 1814-9758 10.15407/bioorganica2020.01 en https://bioorganica.com.ua/index.php/journal/article/view/3/2 Copyright (c) 2020 Maryna Yu. Zhuravlova, Nataliya V. Obernikhina, Stepan G. Pilyo, Maryna V. Kachaeva, Oleksiy D. Kachkovsky, Volodymyr S. Brovarets https://creativecommons.org/licenses/by/4.0 |
| spellingShingle | біологічна афінність 1,3-оксазоли квантово-хімічні розрахунки комплекс [Фарм-БіоМ] п-стекінгова взаємодія водневі зв’язки Zhuravlova, Maryna Yu. Obernikhina, Nataliya V. Pilyo, Stepan G. Kachaeva, Maryna V. Kachkovsky, Oleksiy D. Brovarets, Volodymyr S. In silico дослідження афінності зв’язування фенілзаміщенних 1,3-оксазолів з молекулами білків |
| title | In silico дослідження афінності зв’язування фенілзаміщенних 1,3-оксазолів з молекулами білків |
| title_alt | In silico binding affinity studies of phenyl-substituted 1,3-oxazoles with protein molecules |
| title_full | In silico дослідження афінності зв’язування фенілзаміщенних 1,3-оксазолів з молекулами білків |
| title_fullStr | In silico дослідження афінності зв’язування фенілзаміщенних 1,3-оксазолів з молекулами білків |
| title_full_unstemmed | In silico дослідження афінності зв’язування фенілзаміщенних 1,3-оксазолів з молекулами білків |
| title_short | In silico дослідження афінності зв’язування фенілзаміщенних 1,3-оксазолів з молекулами білків |
| title_sort | in silico дослідження афінності зв’язування фенілзаміщенних 1,3-оксазолів з молекулами білків |
| topic | біологічна афінність 1,3-оксазоли квантово-хімічні розрахунки комплекс [Фарм-БіоМ] п-стекінгова взаємодія водневі зв’язки |
| topic_facet | biological affinity 1,3-oxazoles quantum chemical calculations [Pharm-BioM] complex p-stacking interaction hydrogen bonds біологічна афінність 1,3-оксазоли квантово-хімічні розрахунки комплекс [Фарм-БіоМ] п-стекінгова взаємодія водневі зв’язки |
| url | https://bioorganica.com.ua/index.php/journal/article/view/3 |
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