In silico дослідження афінності зв’язування азотистих біциклічних гетероциклів: пофрагментний підхід
The binding affinity of model aromatic amino acids and heterocycles and their derivatives condensed with pyridine were investigated in silico and are presented in the framework of fragment-to-fragment approach. The presented model describes interaction between pharmacophores and biomolecules. Scrupu...
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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_ | 1871193578022109184 |
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| author | Velihina, Yevheniia S. Obernikhina, Nataliya V. Pilyo, Stepan G. Kachaeva, Maryna V. Kachkovsky, Oleksiy D. Brovarets, Volodymyr S. |
| author_facet | Velihina, Yevheniia S. Obernikhina, Nataliya V. Pilyo, Stepan G. Kachaeva, Maryna V. Kachkovsky, Oleksiy D. Brovarets, Volodymyr S. |
| author_institution_txt_mv | [
{
"author": "Yevheniia S. Velihina",
"institution": "V.P. Kukhar Institute of Bioorganic Chemistry and Petrochemistry of the NAS of Ukraine, 1 Murmanska St., Kyiv, 02094, 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 | Velihina, Yevheniia S. |
| baseUrl_str | https://bioorganica.com.ua/index.php/journal/oai |
| collection | OJS |
| datestamp_date | 2026-07-19T14:56:53Z |
| description | The binding affinity of model aromatic amino acids and heterocycles and their derivatives condensed with pyridine were investigated in silico and are presented in the framework of fragment-to-fragment approach. The presented model describes interaction between pharmacophores and biomolecules. Scrupulous data analysis shows that expansion of the p-electron system by heterocycles annelation causes the shifting up of high energy levels, while the appearance of new the dicoordinated nitrogen atom is accompanied by decreasing of the donor-acceptor properties. Density Functional Theory (DFT) wB97XD/6-31(d,p)/calculations of p-complexes of the heterocycles 1-3 with model fragments of aromatic amino acids, which were formed by p-stack interaction, show an increase in the stabilization energy of p-complexes during the moving from phenylalanine to tryptophan. DFT calculation of pharmacophore complexes with model proton-donor amino acid by the hydrogen bonding mechanism (H-B complex) shows that stabilization energy (DE) increases from monoheterocycles to their condensed derivatives. The expansion of the p-electron system by introducing phenyl radicals to the oxazole cycle as reported earlier [18] leads to a decrease in the stabilization energy of the [Pharm-BioM] complexes in comparison with the annelated oxazole by the pyridine cycle |
| doi_str_mv | 10.15407/bioorganica2020.02.049 |
| first_indexed | 2025-07-17T12:19:42Z |
| format | Article |
| fulltext |
ISSN 1814-9758. Ukr. Bioorg. Acta, 2020, Vol. 15, N 2
UDC 544.6 + 541.138.3: 539.2: 539.216
DOI: https://doi.org/10.15407/bioorganica2020.01.049
49
RESEARCH ARTICLE
In silico study of binding affinity of nitrogenous bicyclic heterocycles:
fragment-to-fragment approach
Yevheniia S. Velihina1, Nataliya V. Obernikhina2*, Stepan G. Pilyo1, Maryna V. Kachaeva1,
Oleksiy D. Kachkovsky1, Volodymyr S. Brovarets1
1V. P. Kukhar Institute of Bioorganic Chemistry and Petrochemistry of the NAS of Ukraine, 1 Murmanska St., Kyiv, 02094, Ukraine
2O. O. Bogomolets National Medical University, 13 Shevchenko Blvd., Kyiv, 01601, Ukraine
Abstract: The binding affinity of model aromatic amino acids and heterocycles and their derivatives condensed with pyridine were
investigated in silico and are presented in the framework of fragment-to-fragment approach. The presented model describes interaction
between pharmacophores and biomolecules. Scrupulous data analysis shows that expansion of the -electron system by heterocycles
annelation causes the shifting up of high energy levels, while the appearance of new the dicoordinated nitrogen atom is accompanied by
decreasing of the donor-acceptor properties. Density Functional Theory (DFT) wB97XD/6-31(d,p)/calculations of -complexes of the
heterocycles 1-3 with model fragments of aromatic amino acids, which were formed by -stack interaction, show an increase in the
stabilization energy of -complexes during the moving from phenylalanine to tryptophan. DFT calculation of pharmacophore complexes
with model proton-donor amino acid by the hydrogen bonding mechanism (H-B complex) shows that stabilization energy (E) increases
from monoheterocycles to their condensed derivatives. The expansion of the -electron system by introducing phenyl radicals to the
oxazole cycle as reported earlier [18] leads to a decrease in the stabilization energy of the [Pharm-BioM] complexes in comparison with
the annelated oxazole by the pyridine cycle.
Keywords: fragment-to-fragment approach; binding affinity; [Pharm-BioM] complex; -stacking interaction; hydrogen bonds.
Introduction
Pharmacologically active compounds, which are based
on the nitrogenous conjugated bicyclic compounds, are
well-known by their vital role in the metabolism of all
living cells [1-3]. These compounds are suitable to design
new perspective molecules using so-called Fragment-Based
Drug Discovery (FBDD) method [4-5]. The simplest
nitrogenous heterocycles (oxazole, pyrazole and their
heterosubsituted and annelated derivatives) were found to
be convenient synthetic intermediates and were often used
as perspective scaffolds in combinatorial medical chemistry
[6-7]. Recently, series of new nitrogenous conjugated
Received:
Revised:
Accepted:
Published online:
10.11.2020
18.11.2020
02.12.2020
30.12.2020
Corresponding author. Tel.: +380-96-225-7764;
e-mail: nataliya.obernikhina@gmail.com (N. V.Obernikhina)
ORCID: 0000-0003-1143-8924
bicyclic molecules were synthesized and were evaluated in
vitro for anticancer and other biological activities [8-9].
The search for new perspective pharmacophores requires
information about the chemical composition, spatial and
electron structure, as well as other properties, including the
affinity to the biomolecules. There is a growing interest in
the in silico studies in search of novel biologically active
molecules. Particularly, development in the field of
quantitative structure-reactivity relationships (QSAR) [10-
12] and molecular docking [7, 10, 13] are gaining traction.
As the next step in the development of the in silico
approach, the approximation based non-empirical quantum-
chemical calculation using the fragment-to-fragment
approach. This technique is being used as opposed to the
traditional methods and is able to evaluate the biological
activity by the chemical structures of the pharmacophore
molecules and the involved fragments of biomolecules [14].
Specifically, the proposed method allows to quantitatively
evaluate a donor/acceptor property of conjugated molecules.
It takes into consideration the relative position of the
frontier molecular orbitals and non-bonding orbitals.
© Velihina Y. S. 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
www.bi oorgan ica .org .ua
https://orcid.org/0000-0003-1143-8924
ISSN 1814-9758. Ukr. Bioorg. Acta, 2020, Vol. 15, N 2
50
All required parameters can be experimentally measured by
photoelectron and absorption spectroscopies [15-17].
Similar in silico approaches discover ways for better
analysis of the binding affinities of the bioactive molecules.
A biological activity depends on the chemical structures
of both a pharmacophore and a target molecules that
includes their 3D geometry and electron structure. Recently,
we reported [18] the influence of the various conjugated
groups (donors, acceptors as well as ambivalent phenyls) in
a mono-cyclic oxazole platform on the electron densities of
substituted derivatives and on their biological activity using
the fragment-to-fragment approach. It was found that the
expansion of the -system by introducing the conjugated
substituents to oxazole platform influenced their biological
activity. Moreover, it was demonstrated that the molecules
that contain acceptor conjugated substituent (-SO2R)
increase the biological activity while donor substituents
(-NR2 or -SR) decrease their activity [8,14].
In the present work we use in silico approach to study a
conjugated system that was formed by condensation of an
oxazole cycle (or its heteroanalogues) with pyridine cycle.
Similar substitution was shown to be effective to increase
anticancer efficiency and other biological activity [9, 19].
Materials and calculation method
Many 1,2-oxazoles have been reported to have a variety
of interesting and significant biological activities [20-22].
Oxazoles conjugated with pyridine at 2-position have been
synthesized and shown antibacterial activities [23]. The
antibacterial and antifungal activities of oxazoles that are
condensed with a benzene ring was also studied [21, 24].
Here, we would like to report in silico study of isoxazole
and its heteroanalogues 1a-c as well as their annelated
derivatives with nitrogen heterocycles 2 and 3 (Table 1).
Table 1. Structure of compounds studied 1-3(a-c).
Compd
N
X N
N
X
N
N
X
1 2 3
X=NH a a a
X=O b b b
X=S c c c
The influence of a heteroatom X on the electronic
structure of the conjugated system and the formation of
hydrogen bonds by a dicoordinated nitrogen atom (inclu-
ding the energies and shape - and n-molecular orbitals
(MOs), donor/acceptor property) will be discussed.
The biological affinity of the potential pharmacophore
(Pharm) should be connected to its ability to form a stable
complex with biomolecule [Pharm-BioM], where BioM is
the fragment of the biomolecule (polypeptide chain). The
complex stability depends on the interaction energy
between both components in [Pharm-BioM] complex. We
have investigated two types of interactions: (1) the -stack
interaction between the conjugated systems of the
components and (2) the formation of hydrogen bonds with
the corresponding functional groups of the amino acids.
The characteristics of the electron structure (optimized
molecular geometry, charge distribution, energies and
molecular orbital shapes) as well as the energy of their
interactions with peptide fragments were calculated using
DFT method with wB97XD functional and 6-31 (d.p.) basis
set (package GAUSSIAN 03 [25]).
Results and Discussion
Intermolecular characteristics of the pharmacophore
molecules
All studied molecules 1-3 are conjugated system.
Therefore, it was no surprise that DFT optimization of
molecular geometry give a planar geometry of the above-
mentioned compounds. The thickness of -electron shell is
3.4 Å. The dimensions of the molecules 1-3 do not exceed
the dimensions of protein fragments. The main regions of
amino acid (-CO-NH-) forms hydrogen bonds in the
polypeptide chain of the protein helix and, therefore, are
inaccessible for the formation of a complex with the mole-
cules of pharmacophores. Therefore, molecules of
pharmacophores 1-3 should interact with protein fragments
that contain flat “aromatic” amino acid groups by the
-stacking mechanism.
In addition, due to the presence of dicoordinated nitrogen
atoms (trtrtr2 configuration) the n-MO occurs among the
highest occupied -orbitals in the electron shell. The
detailed description of these MOs is discussed later in the
section.
The oxazole ligand can form complexes with peptide
fragments thought protein-ligand complex [Pharm-BioM]
interaction [12]. Moreover, it was shown [12, 14] that
biological activity is connected to the frontier orbitals (the
highest occupied molecular orbital (HOMO) and lowest
unoccupied molecular orbital (LUMO). The DFT
calculations showed that the HOMO and LUMO are the
delocalized -orbitals: one orbital n-MO in the monocycle
compounds 1, and two – orbitals n-MO in compounds 2, 3
(Figure 1) are among highest MOs and they correspond to
the lone electron pair (LEP) of these molecules.
As shown in Figure 1a, the replacing nitrogen
(compound 1a) with oxygen (1b) or sulfur (1c) atoms led to
change in HOMO structure that the second -MO becomes
the high energy MO: HOMO-5 HOMO-3. This event
directly effects the ability of substances 1a-1c to form
hydrogen bonds with the corresponding fragment of amino
acids in protein molecules. Annelation with a pyridine ring
in heterocycles 2a-2c (Figure 1b) leads to a redistribution of
electron density in the -orbitals in such a way that
the nitrogen atom (HOMO-2) of the pyridine ring become
Y. S. Velihina, N. V. Obernikhina, S. G. Pilyo et al.
51
Figure 1. Shape of frontier and nearest MO in compounds 1a-1c (a) and compounds 2a-2c (b).
-14
-12
-10
-8
-6
-4
-2
0
2
4
LU MO
HOMO
H 0
H ( - 1)
H ( - 2)
H ( - 5 )
H 0
H ( - 1)
H ( - 2)
H ( - 3)
H ( - 3)
H ( - 2)
H ( - 1)
H 0
L 0
L 0
L 0
L ( +1)
L ( +1)
L ( +1)
E, eV
- level
(1a) (1b) (1c)
(a)
-14
-12
-10
-8
-6
-4
-2
0
2
4
LU MO
HOMO
H ( 0 )
L ( +1)
E, eV
- level
( 2 a)
H ( - 1)
H ( - 2 )
H ( - 3 )
H ( - 5 )
H ( - 2 )
H ( - 1 )
H ( - 3 )
H ( - 5 )
H 0
H ( - 5 )
H ( - 3 )
H ( - 2 )
H ( - 1 )
H 0
L ( +1) L ( +1)
L 0 L 0
L 0
( 2 b) ( 2 c)
( b )
ISSN 1814-9758. Ukr. Bioorg. Acta, 2020, Vol. 15, N 2
52
Figure 2. Shape of frontier and nearest MO in compounds 1b, 2b, 3b.
susceptible to the formation of a hydrogen bond compared
to the nitrogen atom of the five-membered ring (HOMO-3)
of 2a-2c. The shift of the first orbital is observed in oxazolo
pyridine 2b: HOMO-2 HOMO-1. This suggests that for-
mation of hydrogen bond by oxazolopyridine 2b is higher
compared to the compounds 2a and 2c.
When the oxazole ring is annelated with various pyri-
dines (compounds 2b and 3b) insufficiency of HOMO-2 in
isomer 3b is observed. It should also be noted that the
electron density of the -orbital (HOMO-1) in 3b is
concentrated on the nitrogen atom of the pyridine ring
rather than in 2b. Therefore, one can assume that the
stabilization energy of the Н-В complexes is higher for iso-
mer 3b.
Figures 1 and 2 show that the LUMO is a delocalized -
orbital. The energies of both frontier MOs of the studied
molecules are presented in Table 2.
As shown in Table 2, an exchange of heteroatom X (X =
NH, O, S) causes a regular shift in the energy of highest
occupied MO, however this effect decreases with the
expansion of the conjugated system (1 2, 3). In the same
way, the lowest vacant level shifts down both in the initial
molecules 1 and in the annelated derivatives 2, 3. The
energy gap (the distance between the highest occupied MO
and the lowest vacant MO, ) becomes significantly
smaller. In addition, the effects of annelation are different
for both isomers 2, 3.
Table 2. Electron characteristics of compounds 1-3.
Compd X εa, eV b 0
c
HOMO LUMO
1a NH -8.70 2.51 11.21 0.541
1b O -9.43 1.54 10.97 0.465
1c S -9.15 1.15 10.30 0.458
2a NH -8.10 0.36 8.46 0.463
2b O -8.67 -0.43 8.24 0.380
2c S -8.66 -0.37 8.29 0.384
3a NH -8.01 0.41 8.42 0.472
3b O -8.59 -0.44 8.15 0.383
3c S -8.56 -0.42 8.14 0.386
Polyene-15d -6.21 -0.91 5.30 0.500
aε is energy of orbital;
b = (LUMO) - (HOMO);
c0 = [(LUMO) - ]/ [15]; = -3.56137 eV [17];
dsee [15].
This indicates a significant effect on the stacking
interaction between the -systems of both components of
the [Pharm-BioM] complex. We believe that biological
-14
-12
-10
-8
-6
-4
-2
0
2
4
( 2 b ) ( 3 b ) ( 1 b )
- level
LU MO
HOMO
E, eV
H ( - 1 )
L 0
L (+1 )
H ( - 2 )
H ( - 3 )
H 0
H 0 H 0
H ( - 1 ) H ( - 1 )
H ( - 2 ) H ( - 2 )
H ( - 3 ) H ( - 3 )
H ( - 5 )
H ( - 5 )
L 0 L 0
L (+1 ) L (+1 )
Y. S. Velihina, N. V. Obernikhina, S. G. Pilyo et al.
53
activity should be associated primarily with the donor-
acceptor properties of the interacting components.
Naturally, this effect involve positive contributions from the
frontier MOs. In addition, the position of the frontier MO
directly affects the donor and acceptor ability of the
conjugated molecules.
A change in the chemical composition causes the change
in relative position of the energy gap. The energy gap can
be quantitatively characterized by its position with respect
to the non-bonding level (Fermi level of -electron) [17];
such method will correlate with the donor-acceptor
property. Recently, it was proposed to call it the donor-
acceptor parameter (DAP); this parameter (signed as an
index 0) can be calculated quantitatively [15].
The value of neutral conjugated molecules (for
example the long unsubstituted polyenes or acene series)
corresponds to such dispositions of the frontier levels when
the donor and acceptor properties are mutually balanced and
therefore, 0 = 0.5, i.e. the energy gap is located
symmetrically with respect to the imaginary level [17]. If
the energy gap is shifted up, then the parameter would
increase and 0> 0.5; these relative positions of the frontier
levels indicate the predominate donor properties of the
conjugated molecules. And vice versa, if the parameter 0 <
0.5 and the energy gap is shifted down, then the molecule is
predominately acceptor [14-17]. The calculated values 0
for compounds 1-3 are presented in Table 2.
The data analysis shows that only compound 1a
(X = NH) is a true donor system: the middle of the energy
gap is shifted up relative to the non-bonding level and
therefore, 0 > 0.5. In the compounds 1b (X = O) and 1c
(X = S) the energy gap is shifted down, so that they become
weak acceptors (0 0.46). As shown in Table 2 the
nitrogenous cycle causes the energy gap to shift down so
that all derivatives 2, 3 become acceptor molecules. It can
been seen from Table 2 the difference between both isomers
2 and 3 is insignificant: comparing the parameter 0 for
both corresponding molecules with the same heteroatom X
shows that their acceptor capacity should not differ
significantly from each other.
Dicoordinated nitrogen atoms with their LEPs can be
involved in the formation of the hydrogen bonds. Their
atomic charges are presented in Table 3. Firstly, the atomic
charge of the nitrogen atom significantly depends on the
heteroatom X caused by the redistribution of electron
densities in the atoms of the compounds 1-3: the
calculations give the minimal negative charge at the
dicoordinated nitrogen atom in the oxazole (X = O), while
the maximum charge is found in the thiazole (X = S). The
transition to the corresponding annelated derivatives 2, 3 is
accompanied by a significant increase in atomic charges at
the dicoordinated nitrogen of the five-membered cycle: the
difference between the two isomers is insignificant. In
addition, the calculations show that that charges at the
nitrogen atom in the six-membered cycle differ from the
charges in the five-membered cycle and are weakly
sensitive to the nature of the heteroatom X. Besides, these
charges are not sensitive to the expansion of -electronic
system.
The geometry of the corresponding level to n-MO (LEP)
was also calculated. As shown in Figure 2 and Figure 3 this
orbital is directed perpendicularly to -MOs and, therefore,
can interact with the -orbitals. When two n-MOs appear in
bicyclic molecules 2, 3, they interact with each other (and
with -MOs); then n-MOs are mixed and are localized on
both dicoordinated nitrogen atoms. The positions and
energies of the corresponding n-levels are summarized in
Table 3.
Table 3. Charges at nitrogen atoms and energies of n-MOs
in compounds 1-3.
Compd N(5)a N(6)b
zc,
e.u.
n-MO d,
eV
zc,
e.u.
n-MO d,
eV
1a -0.29 HOMO-2 -10.05 - - -
1b -0.16 HOMO-2 -10.69 - - -
1c -0.49 HOMO-2 -10.23 - - -
2a -0.39 HOMO-3 -10.63 -0.50 HOMO-2 -8.99
2b -0.26 HOMO-3 -11.22 -0.49 HOMO-1 -9.56
2c -0.58 HOMO-3 -10.92 -0.48 HOMO-2 -9.28
3a -0.39 HOMO-3 -10.41 -0.46 HOMO-1 -9.06
3b -0.26 HOMO-3 -10.91 -0.45 HOMO-1 -9.60
3c -0.57 HOMO-3 -10.49 -0.45 HOMO-1 -9.41
aN(5) is Nitrogen atom in five-membered cycle compounds 1-3;
bN(6) is Nitrogen atom in six-membered cycle compounds 2-3;
cz is charge at atoms N(5) and N(6) respectively;
d is energy of corresponding n-MO e.u. is electron units.
In the monocyclic molecules 1, the energy of n-MO
decreases in the series 1a-1c (X = NH, O, S). In bicyclic
systems 2, 3 with two LEPs, the splitting level causes an
appearance of two split levels; their energies are weakly
sensitive to isomerization, especially the second split n-
level. The first split level in the compounds 2 are slightly
shifted lower than in the corresponding compounds 3. Thus,
the sensitivity of the MO properties of the heterocycles 1-3
depending on their configuration and should be manifested
in the interaction with the biomolecules, i.e., in the binding
affinity of the heterocycles 1-3.
Intermolecular binding affinity: interaction between
pharmacophore and biomolecule fragments
The binding affinity of any potential pharmacophore can
be define by its ability to effectively interact with certain
fragments of a biological molecule so that the pharma-
cophore (Pharm) and biomolecule (BioM) can generate a
stable complex: [Pharm] + [BioM] [Pharm-BioM].
Therefore, a pharmacological effect can occur. The effecti-
veness of this appearance should depend on the stability of
the complex [Pharm-BioM], which, in turn, depends on the
geometric complementarity of both complex components. It
is well establish [26] that proteins usually form branched
polypeptide chains connected by numerical hydrogen bonds
ISSN 1814-9758. Ukr. Bioorg. Acta, 2020, Vol. 15, N 2
54
(mutual interactions of -CO-NH- fragments). Therefore, the
oxygen and nitrogen atoms of these groups cannot interact
with foreign molecules (pharmacophores). However, there
are fragments of proteinogenic amino acids that are
available for intermolecular interactions with the
pharmacophore.
The main feature of the studied heterocycles 1-3 is their
branched system of -electrons. The effective electron
interaction with non-conjugated amino acid fragments is
evidently not effective; we can assume that the aqueous
environment forces all organic molecules to interact with
each other. On the contrary, interactions with conjugated
molecular fragments can make an additional contribution
(by stacking interaction) to the overall stability of [Pharm-
BioM] complex. There are four aromatic natural amino
acids: Phe, Tyr, Trp and His. These peptide fragments are
spatially commensurable with the conjugated molecules 1-
3, and therefore their interaction can additionally stabilized
the [Pharm-BioM] complex, i.e., increase the binding
affinity.
As seen from the chemical formulas 1-3 that the studied
molecules contain one (compounds 1) or two (compounds
2, 3) dicoordinated nitrogen atoms with LEPs; these
electron pairs (located perpendicular to the conjugated
system) can efficiently generate hydrogen bonds with
aminoacid fragments containing -OH or -NH2 or -SH
groups and, therefore, can produce a specific complex –
H-B complex that is formed by hydrogen bonds. After that,
the ability to form the-complex will be considered as a -
electron affinity component; similarly, the ability to form a
complex by the hydrogen bonds can be called as H-B
affinity component.
These properties can be calculated by a direct quantum-
chemical modeling. Thus, many [Pharm-BioM] interactions
can be modeled by interactions between the pharmacophore
and some fragments of the biological molecules while
taking into consideration the complementarity of the Pharm
components. Similarly to a well-known FBDD approach [4]
we can call our method a fragment-to-fragments approach.
Not only the chemical structures of the pharmacophore
fragments are considered, but also the chemical structures
of the biomolecule fragments are considered.
--Interaction in stacking [Pharm-BioM] complex
In this paper, we have examined the intermolecular
interaction in the -electron complex that is generated by
oxazole and its heteroanalogues 1 as well as by both
isomers 2 and 3. Their chemical composition and structural
characteristics should influence the stability of such
complex. Generally, the interaction of two -electron
systems can be estimated by the relative positions of the
molecular levels of both molecules as well as the
overlapping of their -systems; in MO approximation, the
interaction energy E is quantitatively calculated in the
approximation of the interaction of MO [18].
In our study of the --density interaction the only two
amino acid fragments were selected: phenyl-alanine (Phe)
and tryptophan (Trp) acids. Then, we simulated the outside
radicals by the model molecules: Het-CH3, where Het is the
conjugated heterocycle of the corresponding amino acids.
So, the phenylalanine is modeled by the toluene (Phe-CH3);
its -affinity parameter 0 = 0.52 (0 = 0.53 for the phenyl
alanine acid). The tryptophan is modeled by
3-methyl benzoindolenine (BIn-CH3); its -affinity
parameter 0 = 0.60 (0 = 0.62 for the corresponding
tryptophan amino acid).
In the studied [Pharm-BioM] complexes, the distance
between the components (i.e., between planes of the
molecules 1-3 and plane of the aromatic fragments is
initially 3.4 Å) similar to DNA helix [27] or in polymethine
dye aggregates [28]. The initial mutual arrangements in the
-complex of the molecule 1 (X = O) and model fragments
are shown in Figure 4 (in two planes):
To simplify, the binding energy (Ebinding) in the complex
is calculated as a difference between the total energy of the
generated [Pharm-BioM] complex and the energies of both
its components, i.e., in a stable complex, the binding energy
is additional stabilization energy [29-30]. The calculated
binding energies for the optimized complex are summarized
in Table 4. The areas of the bicycle molecules 1, 2 and
monocycle 3 are incommensurable, therefore we were not
able to compare their stabilizations energies.
The calculations show that all complexes should be
stable: the formation of complexes with pharmacophore and
model biofragments leads to a decrease in the total energy
of the generated complex compared to the energies of the
original components. Perhaps the absolute values of the
stabilization energies, E, were slightly overestimated.
Thus, the proposed approach allows to study the
dependence of the binding affinity on molecular topology,
and therefore, to establish the general regularities between
chemical structure of pharmacophores and various
components of their biological activity. Thus, it can
concluded that the presence of a branched conjugated
system increases their stability of -complexes formation
with the corresponding fragments of biomolecules.
Regarding the chemical structure of the studied
molecules, the data in Table 4 show that the influence of
substitution of heteroatom X on the calculated stabilization
energy in the [Compound:Phe-CH3] complex is
insignificant, while similar [Compound:BIn-CH3] complex
are more sensitive to the nature of heteroatom X. This effect
may be explained by the greater overlap of the conjugated
system of both complex components in [Compound:BIn-
CH3]. In addition, we should consider that tryptophan
shows more donor properties than phenylalanine. Therefore
the generated [Compound:BIn-CH3] complex with the
acceptor molecules 2 and 3 should be more stable compare
to the [Compound:Phe-CH3] complex with the same
pharmacophores. Indeed, the performed calculations
confirm this assumption: transition from a complex with
model phenylalanine to a complex with a model tryptophan
increases the stabilization energy of both complexes.
Compounds 3a-c form more stable -complexes with model
phenylalanine compare to 2a-c. In contrast to model trypto-
Y. S. Velihina, N. V. Obernikhina, S. G. Pilyo et al.
55
a
b
Figure 4. Mutual arrangement of both components in --complex [Pharm-BioM]: a) compound 2 with phenylalanine residue in X-Y
plane; b) compound 2 with a phenylalanine residue in X-Z plane.
a b
c d
Figure 5. Possible types of H-B complex [Pharm-BioM] between CH3OH and oxazole derivatives 1b (a) and 3b (b-d).
ISSN 1814-9758. Ukr. Bioorg. Acta, 2020, Vol. 15, N 2
56
Table 4. Stability of -complexes compounds 2, 3 with model biofragments.
Compd X Emol
a, a.u. [Compound:Phe-CH3] [Compound:BIn-CH3]
Ecompl
b, a.u. Ec,
kcal/mol
Ecompl, a.u. E,
kcal/mol
2a NH -395.7 -667.2 -7.15 -798.8 -9.55
2b O -415.6 -687.0 -7.93 -818.6 -10.80
2c S -738.6 -1010.1 -7.65 -1141.6 -8.82
3a NH -395.7 -667.2 -8.89 -798.8 -12.88
3b O -415.6 -687.0 -9.21 -818.6 -9.36
3c S -738.6 -1010.1 -9.41 -1141.6 -12.49
Phe-CH3 -271.5
BIn-CH3 -403.0
aEcompd is total energy of compounds;
bEcompl is total energy of [Pharm-BioM] complex;
cE is binding energy increases only the stability of the formed complex.
phan, where the stabilization energy of the -complex is
sensitive to the heteroatom but not to the isomers.
Hydrogen bonding
Some amino acids such as lysine, arginine, histidine have
groups containing active hydrogen (-NH, -OH, and -SH)
and can form hydrogen bonds. On the other hand, the
oxazolo-pyridines 2-3 contain the dicoordinated nitrogen
atoms with LEP that promote such non-covalent bonds
interaction as an acceptor. The hydrogen bond energies of
the oxazole 1 (and its hetaryl-containing analogues) were
calculated. Fragments of the donor components were
modeled with methyl groups, optimistically assuming that
the effect of non-conjugated part of the amino acids is
negligible, i.e., the biocomponent in H-B complexes is
modeled by the simpler molecule: H3C-Y where Y = OH,
NH, SH.
For annelated molecules 2 and 3, there are two possible
ways to form a model H-B complex, fixed by hydrogen
bonds. Possible complexes of the model molecule H3C-O-H
with oxazoles 1b, 2b, 3b as well as with its annelated
derivatives are shown in Figure 5.
At the beginning we calculated the H-B complex with
simpler molecules 1a-c. These molecules can form one
hydrogen bond with the dicoordinated nitrogen atom. The
calculated stabilization energies of the H-B complexes are
summarized in Table 5.
The length of the hydrogen bond in the formed
[Compound 1:H-X] complexes depends on the nature of
compounds 1a, 1b, 1c, and are about l = 2 2.3 Å;
although the negative charge at the dicoordinated nitrogen
atom varies greatly due to the nature of the heteroatom X in
oxazole hetaryl-containing analogues (Table 2).
Analysis of the calculated energies of hydrogen bonds in
the complexes [Compound 1:H-X] shows that oxazole 1b
gives the maximum value to the complex with the model
molecule CH3OH. The transition from isoxazole 1b to
isopyrazole 1a increases the stabilization of such a
complex, while the transition to isothiazole 1c reduces the
stability of the formed complex on 0.7 kcal/mol.
At the same time, the effect of substitution of the proton-
donor molecule CH3OH by an amino analog (CH3NH2) or
by a thiol analog (CH3SH) can be seen in Table 4. It is
accompanied by a decrease in binding energy in
[Compound 1b:H-X] complex.
Chemical modification of 1a-c by the condensed
acceptor pyridine cycle significantly affects the affinity of
the pharmacophore. The calculated binding energies of
possible H-B complexes of 2a-c, 3a-c with the model donor
component H3C-OH are summarized in Table 6.
First of all, the calculated values of E for the
[Compound 2:H-O-CH3] complex and [Compound 3:
H-O-CH3] complex with a hydrogen bond included a di-
coordinated nitrogen atom in the five-membered oxazole
cycle shown in Table 5, with the corresponding values for
the [Compound 1:H-O-CH3] complex in Table 4. The
annelation of the pyrazole 1a with pyridine produce the
compound 2a that practically does not change the binding
energy for the H-B complex, whereas a similar H-B
complex which the corresponding compound 3a is
appreciable destabilized by 2.5 kcal/mol.
The stabilization energy of hydrogen bond formation
azoles 1-3 are sensitive to the expansion of the conjugated
system of the pharmacophore; therefore, the transition from
molecule 1b (X = O) to the corresponding 2b (X = O) or to
the 3b (X = O) is accompanied by an increase in the
generated the H-B complex with the same hydrogen bond
formation site by approximately 2 kcal/mol. At the same
time, for the thiol-containing hetero analogues, pyridine
cycle’s annelation leads to the significant increase in the
stabilization energy of the corresponding H-B complex up
to 3.0 kcal/mol.
Y. S. Velihina, N. V. Obernikhina, S. G. Pilyo et al.
57
Table 5. Hydrogen bond energy of complex [Compound 1:H-X] with model methanol, methylamine, and methanethiol.
Complex H-X la, Å Ecompd
b, a.u. Ecompl
c, a.u. Ed,
kcal/mol
[compound 1b:H-X] H-O-CH3 2.067 -245.9 -361.6 -8.09
[compound 1b:H-X] H2N-CH3 2.295 -245.9 -341.8 -4.16
[compound 1b:H-X] H-S-CH3 2.268 -245.9 -684.6 -3.72
[compound 1a:H-X] H-O-CH3 2.062 -226.1 -341.8 -12.06
[compound 1c:H-X] H-O-CH3 1.988 -569.0 -684.7 -7.30
H2N-CH3 -95.8 - -
H-O-CH3 -115.7 - -
H-S-CH3 -438.7 - -
al is the length of the hydrogen bond;
bEcompd is the energy of the compounds;
cEcompl is the energy of the [Compound:H-X] complex;
dE is the stabilization energy.
Table 6. Stability of hydrogen bond energy [Compound:H-O-CH3] complex with compounds 2, 3.
Complex [Compounds 2, 3:H-O-CH3] by N(5)a [Compounds 2, 3:H-O-CH3] by N(6)b
l, Å Ecompl, a.u. E,
kcal/mol
l, Å Ecompl, a.u. E,
kcal/mol
[compound 2a:H-O-CH3] 2.062 -511.4 -12.31 1.955 -511.4 -12.22
[compound 2b:H-O-CH3] 2.040 -531.3 -10.11 1.992 -531.3 -8.91
[compound 2c:H-O-CH3] 2.003 -854.3 -10.43 1.973 -854.3 -11.65
[compound 3a:H-O-CH3] 1.983 -511.4 -9.93 1.937 -511.4 -9.96
[compound 3b:H-O-CH3] 2.047 -531.3 -9.58 1.966 -531.3 -9.65
[compound 3c:H-O-CH3] 2.012 -854.3 -9.98 1.954 -854.3 -9.82
a[compound:H-O-CH3] by N(5) involves dicoordinated nitrogen in five-membered cycle of compounds 2,3
b[compound:H-O-CH3] by N(6) involves dicoordinated nitrogen in six-membered cycle of compounds 2,3.
Compared to the five-membered nitrogenous circles,
compounds 2, 3 contain additional LEP in the di-
coordinated nitrogen atom in the pyridine cycle. We
compared two possible mechanisms of the H-B complex
generation by N(5) and N(6) atoms. These data are
presented in Table 6. As we can see that the stability of the
H-B complexes for both isomers 2 and 3 are close to each
other.
The complexes 2 [Compound 2:H-O-CH3] are more
stable than complexes 3 [Compound 3:H-O-CH3], except
for H-B complex by N(6) azole derivative: compound 3b is
more stable ( 1 kcal/mol).
It should be noted that the annelation and the
heterosubstitution have a little effect on the length of the
formed hydrogen bond, especially in compounds 2 and 3.
Thus, we can assume that the annelation of heterocycles 1а-
1с with a pyridine cycle leads to greater stabilization of the
complex and, consequently, to increasing the binding
affinity.
Conclusions
Scrupulous in silico study of the conjugated
pharmacophores based on heteroazoles and their
pyridocondenced derivatives, as part of a fragment-to-
fragment approach, shows that the expansion of the -
electron system by annelation causes a shift of high HOMO,
while the appearance of a new dicoordinated nitrogen atom
is accompanied by a decrease in the donor-acceptor
properties. Numerical calculations of possible complexes of
the studied heterocycles 1-3 with model fragments of
biomolecules demonstrated the increase in the stabilization
energy of the [Pharm-BioM] -complexes during the
transition from phenylalanine to the high donor triptophan.
Calculations of stabilization energies of H-B complexes
with model proton-donor biomolecules show that the Е
increases upon annelation of oxazole (and its
heteroanalogues) with pyridine cycle. It should be noted
that the expansion of the -electron system by introducing
phenyl radicals to the oxazole cycle as reported earlier [18]
ISSN 1814-9758. Ukr. Bioorg. Acta, 2020, Vol. 15, N 2
58
leads to a decrease in the stabilization energy of the
[Pharm-BioM] complexes in comparison with the annelated
oxazole by the pyridine cycle.
Notes
The authors declare no conflict of interest.
Author contributions. Ye. S. V.: 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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Y. S. Velihina, N. V. Obernikhina, S. G. Pilyo et al.
59
In silico дослідження афінності зв’язування азотистих біциклічних гетероциклів:
пофрагментний підхід
Є. С. Велігіна1, Н. В. Оберніхіна2*, С. Г. Пільо2, М. В. Качаєва2, О. Д. Качковський2, В. С. Броварець2
1Інститут біоорганічної хімії та нафтохімії ім. В. П. Кухаря НАН України, вул. Мурманська, 1, Київ, 02094, Україна.
2Національний медичний університет імені О. О. Богомольця, бульв. Т. Шевченка, 13, Київ, 01601, Україна.
Резюме: В рамках підходу «фрагмент до фрагменту» представлені іn silico результати біологічної спорідненості гетероциклів та їх похідних,
конденсованих з піридином. Така модель використовується для дослідження взаємодії між фармакофорами та біомолекулами. Детальний аналіз
показує, що розширення -електронної системи шляхом конденсації гетероциклічних систем молекулою піридину викликає зміщення вищих
зайнятих молекулярних рівнів, тоді як поява додаткового двох-координованого атома азоту супроводжується зменшенням їх донорно-
акцепторних властивостей. Розрахунки можливих -комплексів досліджуваних гетероциклів 1-3 із модельними фрагментами ароматичних
амінокислот, утворених за механізмом -стекової взаємодії, показують збільшення енергії стабілізації -комплексів при переході від
фенілаланіну до триптофану. Розрахунок енергій стабілізації комплексів фармакофорів з модельними протон-донорними залишками амінокислот
за механізмом водневого зв’язку (H-B комплекс) показує, що Е збільшується при переході від моногетероциклів до їх конденсованих похідних.
Розширення -електронної системи сполук 1 піридиновим циклом зменшило енергію стабілізації -комплексів та H-B комплексів у порівнянні з
розширенням -електронної системи, шляхом введення фенільного радикала у 2 або 5 положення оксазольного кільця, описаних раніше
оксазолів [18].
Ключові слова: підхід «фрагмент до фрагмента»; афінність зв’язування; комплекс [Фармакофор-Біомолекула]; -стекінгова взаємодія; водневі
зв’язки.
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| 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 |
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| spelling | oai:ojs2.bioorganica.com.ua:article-412026-07-19T14:56:53Z In silico study of binding affinity of nitrogenous bicyclic heterocycles: fragment-to-fragment approach In silico дослідження афінності зв’язування азотистих біциклічних гетероциклів: пофрагментний підхід Velihina, Yevheniia S. Obernikhina, Nataliya V. Pilyo, Stepan G. Kachaeva, Maryna V. Kachkovsky, Oleksiy D. Brovarets, Volodymyr S. fragment-to-fragment approach binding affinity [Pharm-BioM] complex п-stacking interaction hydrogen bonds підхід «фрагмент до фрагмента» афінність зв’язування комплекс [Фармакофор-Біомолекула] п-стекінгова взаємодія водневі зв’язки The binding affinity of model aromatic amino acids and heterocycles and their derivatives condensed with pyridine were investigated in silico and are presented in the framework of fragment-to-fragment approach. The presented model describes interaction between pharmacophores and biomolecules. Scrupulous data analysis shows that expansion of the p-electron system by heterocycles annelation causes the shifting up of high energy levels, while the appearance of new the dicoordinated nitrogen atom is accompanied by decreasing of the donor-acceptor properties. Density Functional Theory (DFT) wB97XD/6-31(d,p)/calculations of p-complexes of the heterocycles 1-3 with model fragments of aromatic amino acids, which were formed by p-stack interaction, show an increase in the stabilization energy of p-complexes during the moving from phenylalanine to tryptophan. DFT calculation of pharmacophore complexes with model proton-donor amino acid by the hydrogen bonding mechanism (H-B complex) shows that stabilization energy (DE) increases from monoheterocycles to their condensed derivatives. The expansion of the p-electron system by introducing phenyl radicals to the oxazole cycle as reported earlier [18] leads to a decrease in the stabilization energy of the [Pharm-BioM] complexes in comparison with the annelated oxazole by the pyridine cycle В рамках підходу «фрагмент до фрагменту» представлені іn silico результати біологічної спорідненості гетероциклів та їх похідних, конденсованих з піридином. Така модель використовується для дослідження взаємодії між фармакофорами та біомолекулами. Детальний аналіз показує, що розширення p-електронної системи шляхом конденсації гетероциклічних систем молекулою піридину викликає зміщення вищих зайнятих молекулярних рівнів, тоді як поява додаткового двох-координованого атома азоту супроводжується зменшенням їх донорно-акцепторних властивостей. Розрахунки можливих p-комплексів досліджуваних гетероциклів 1-3 із модельними фрагментами ароматичних амінокислот, утворених за механізмом p-стекової взаємодії, показують збільшення енергії стабілізації p-комплексів при переході від фенілаланіну до триптофану. Розрахунок енергій стабілізації комплексів фармакофорів з модельними протон-донорними залишками амінокислот за механізмом водневого зв’язку (H-B комплекс) показує, що DE збільшується при переході від моногетероциклів до їх конденсованих похідних. Розширення p-електронної системи сполук 1 піридиновим циклом зменшило енергію стабілізації p-комплексів та H-B комплексів у порівнянні з розширенням p-електронної системи, шляхом введення фенільного радикала у 2 або 5 положення оксазольного кільця, описаних раніше оксазолів [18] V.P. Kukhar Institute of Bioorganic Chemistry and Petrochemistry of the National Academy of Sciences of Ukraine 2020-12-30 Article Article application/pdf https://bioorganica.com.ua/index.php/journal/article/view/41 10.15407/bioorganica2020.02.049 Ukrainica Bioorganica Acta; Vol. 15 No. 2 (2020): Ukrainica Bioorganica Acta; 49-59 Ukrainica Bioorganica Acta; Том 15 № 2 (2020): Ukrainica Bioorganica Acta; 49-59 1814-9766 1814-9758 10.15407/bioorganica2020.02 en https://bioorganica.com.ua/index.php/journal/article/view/41/40 Copyright (c) 2020 Yevheniia S. Velihina, Nataliya V. Obernikhina, Stepan G. Pilyo, Maryna V. Kachaeva, Oleksiy D. Kachkovsky, Volodymyr S. Brovarets https://creativecommons.org/licenses/by/4.0 |
| spellingShingle | підхід «фрагмент до фрагмента» афінність зв’язування комплекс [Фармакофор-Біомолекула] п-стекінгова взаємодія водневі зв’язки Velihina, Yevheniia S. Obernikhina, Nataliya V. Pilyo, Stepan G. Kachaeva, Maryna V. Kachkovsky, Oleksiy D. Brovarets, Volodymyr S. In silico дослідження афінності зв’язування азотистих біциклічних гетероциклів: пофрагментний підхід |
| title | In silico дослідження афінності зв’язування азотистих біциклічних гетероциклів: пофрагментний підхід |
| title_alt | In silico study of binding affinity of nitrogenous bicyclic heterocycles: fragment-to-fragment approach |
| title_full | In silico дослідження афінності зв’язування азотистих біциклічних гетероциклів: пофрагментний підхід |
| title_fullStr | In silico дослідження афінності зв’язування азотистих біциклічних гетероциклів: пофрагментний підхід |
| title_full_unstemmed | In silico дослідження афінності зв’язування азотистих біциклічних гетероциклів: пофрагментний підхід |
| title_short | In silico дослідження афінності зв’язування азотистих біциклічних гетероциклів: пофрагментний підхід |
| title_sort | in silico дослідження афінності зв’язування азотистих біциклічних гетероциклів: пофрагментний підхід |
| topic | підхід «фрагмент до фрагмента» афінність зв’язування комплекс [Фармакофор-Біомолекула] п-стекінгова взаємодія водневі зв’язки |
| topic_facet | fragment-to-fragment approach binding affinity [Pharm-BioM] complex п-stacking interaction hydrogen bonds підхід «фрагмент до фрагмента» афінність зв’язування комплекс [Фармакофор-Біомолекула] п-стекінгова взаємодія водневі зв’язки |
| url | https://bioorganica.com.ua/index.php/journal/article/view/41 |
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