In silico дослідження взаємодії гетероциклічних основ з пептидними групами білків: пофрагментний підхід
The binding affinity of model peptide moieties (Pept) and heterocyclic bases involving 1,3-oxazoles that are condensed with pyridine and pyrimidine as pharmacophores (Pharm) was investigated in silico and analyzed within the “fragment-to-fragment” approach. The anellation of the heterocyclic rings i...
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V.P. Kukhar Institute of Bioorganic Chemistry and Petrochemistry of the National Academy of Sciences of Ukraine
2021
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Ukrainica Bioorganica Acta| _version_ | 1871193583043739648 |
|---|---|
| author | Velihina, Yevheniia S. Obernikhina, Nataliya V. Pilyo, Stepan G. Kachaeva, Maryna V. Kachkovsky, Oleksiy D. |
| author_facet | Velihina, Yevheniia S. Obernikhina, Nataliya V. Pilyo, Stepan G. Kachaeva, Maryna V. Kachkovsky, Oleksiy D. |
| 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; O.O. Bogomolets National Medical University, 13 Shevchenko Blvd., Kyiv, 01601, Ukraine"
},
{
"author": "Nataliya V. Obernikhina",
"institution": "V.P. Kukhar Institute of Bioorganic Chemistry and Petrochemistry of the NAS of Ukraine, 1 Murmanska St., Kyiv, 02094, Ukraine; 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; O.O. Bogomolets National Medical University, 13 Shevchenko Blvd., Kyiv, 01601, 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; O.O. Bogomolets National Medical University, 13 Shevchenko Blvd., Kyiv, 01601, 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; O.O. Bogomolets National Medical University, 13 Shevchenko Blvd., Kyiv, 01601, Ukraine"
}
] |
| author_sort | Velihina, Yevheniia S. |
| baseUrl_str | https://bioorganica.com.ua/index.php/journal/oai |
| collection | OJS |
| datestamp_date | 2026-07-19T14:56:54Z |
| description | The binding affinity of model peptide moieties (Pept) and heterocyclic bases involving 1,3-oxazoles that are condensed with pyridine and pyrimidine as pharmacophores (Pharm) was investigated in silico and analyzed within the “fragment-to-fragment” approach. The anellation of the heterocyclic rings increasing their acceptor properties is accompanied by gaining stability of the [Pharm-Pept] complexes formed by the p-stack interaction. It was found that elongation of the polypeptide chain led to a twofold increase of the stabilization energy of the [Pharm-Pept] complexes. The stability of the hydrogen bonding ([HB]) [Pharm-BioM] complexes formed by means of the interaction between the dicoordinated nitrogen atom of the heterocycle and the functional groups of peptide amino acids (-OH, -NH2, -SH) was evaluated. It was demonstrated that [HB]-complexes that were formed by hydrogen bonds formation with amino acid that contained OH groups had the largest stabilization effect. The anellation with pyridine and pyrimidine rings led to stability increase of the complexes formed by the hydrogen bonding mechanism. The binding energy of [HB]-complexes for compounds 2b and 3 with a "free" peptide bond of the extended part of the protein is lower compared to amino acids with OH-functional groups. On the contrary, the binding energy of compound 4 with peptides was 2 kcal/mol higher. Compound 4 demonstrated the most pronounced biological activity in vitro studies. |
| doi_str_mv | 10.15407/bioorganica2021.01.034 |
| first_indexed | 2025-07-17T12:19:46Z |
| format | Article |
| fulltext |
ISSN 1814-9758. Ukr. Bioorg. Acta, 2021, Vol. 16, N 1
UDC 544.6 + 541.138.3: 539.2: 539.216
DOI: https://doi.org/10.15407/bioorganica2021.01.034
34
Ukrainica Bioorganica Acta
www.bi oorgan ica .org .ua
RESEARCH ARTICLE
In silico study the interaction of heterocyclic bases with peptide moieties
of proteins in “fragment-to-fragment” approach
Yevheniia S. Velihina1, Nataliya V. Obernikhina2*, Stepan G. Pilyo1, Maryna V. Kachaeva1,
Oleksiy D. Kachkovsky1
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 peptide moieties (Pept) and heterocyclic bases involving 1,3-oxazoles that are condensed with
pyridine and pyrimidine as pharmacophores (Pharm) was investigated in silico and analyzed within the “fragment-to-fragment” approach.
The anellation of the heterocyclic rings increasing their acceptor properties is accompanied by gaining stability of the [Pharm-Pept]
complexes formed by the -stack interaction. It was found that elongation of the polypeptide chain led to a twofold increase of the
stabilization energy of the [Pharm-Pept] complexes. The stability of the hydrogen bonding ([HB]) [Pharm-BioM] complexes formed by
means of the interaction between the dicoordinated nitrogen atom of the heterocycle and the functional groups of peptide amino acids
(-OH, -NH2, -SH) was evaluated. It was demonstrated that [HB]-complexes that were formed by hydrogen bonds formation with amino
acid that contained OH groups had the largest stabilization effect. The anellation with pyridine and pyrimidine rings led to stability
increase of the complexes formed by the hydrogen bonding mechanism. The binding energy of [HB]-complexes for compounds 2b and 3
with a "free" peptide bond of the extended part of the protein is lower compared to amino acids with OH-functional groups. On the
contrary, the binding energy of compound 4 with peptides was 2 kcal/mol higher. Compound 4 demonstrated the most pronounced
biological activity in vitro studies.
Keywords: fragment-to-fragment approach; peptide bond; biological affinity; [Pharm-BioM] complex; -stacking interaction; hydrogen
bonding.
Introduction
The heterocyclic ring systems containing both nitrogen
and oxygen, such as substituted 1,3-oxazoles, are very
suitable for use in drug design and library design, which has
allowed the introduction of a number of novel pharma-
cological agents in medical practice (see for example
reviews [1-2]). The 1,3-oxazoles with branched conjugated
systems have revealed higher biological activity including
antibacterial and antiviral activities [3-4], and multiple drug
resistance pump inhibition [5-6].
Received:
Revised:
Accepted:
Published online:
27.04.2021
06.05.2021
08.05.2021
30.06.2021
Corresponding author. Tel.: +380-96-225-7764;
e-mail: nataliya.obernikhina@gmail.com (N. V. Obernikhina)
ORCID: 0000-0003-1143-8924
It was found that these compounds can be considered as
a promising component in the development of new
biologically active substances that exhibit antitumor activity
in a strong dependence on the nature of the substituents in
the heterocycle [7-10]. This has enabled the wide
introduction of novel pharmacological remedies in clinical
practice [11-12]. The QSAR models have been developed
for a large series of 1,3-oxazole derivatives showing
inhibitory effect on some cancer cell lines and
demonstrating a good correlation between many descriptors
and biological activity [14].
Determination of a mechanism of multiple ligand
binding affinity for amino acids in binding and regulatory
proteins is currently an actual task for researches. Binding
cavities on protein surfaces are important for protein
function because they are usually the sites at which a
protein binds to other biological macromolecules such as
other proteins and nucleic acids, or small molecules such as
metabolites and pharmacophores [15].
© 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.
Y. S. Velihina, N. V. Obernikhina, S. G. Pilyo et al.
35
Table 1. Chemical structures of the compounds 1-2(a-c) and 3-6.
Compd N
X
(Z) (Z)
N
X
(Z)
N
N
O
(Z)
N
NN
O
H3C N
CH3
O
H
H3C N
O
H
N
CH3
H
O
1 2 3 4 5 6
X=NH a a - - - -
X=O b b - - - -
X=S c c - - - -
Therefore, in order to minimize energy of formation of
the Pharmophore Biomolecule ([Pharm-BioM]) complex,
structure and electronic properties of the pharmacophore
should be as close as possible to the corresponding real
protein cavities [16]. The interaction between ligands and
proteins usually induces changes in structure and
conformational flexibility of the protein. These
modifications are due to the coupling of unfolding with
binding equilibrium [17-18]. In this regard, it could be
expected that modifications in protein stability correlate
with changes in the protein packaging caused by ligand-
pharmacophore binding due to various types of bond
formation, including the formation of a pharmacophore-
ligand bond with a “free” peptide bond, not untwisted part
of the protein.
Over the past two decades, the Fragment-Based Drug
Discovery (FBDD) strategy has been considered in the
pharmaceutical industry as a successful key technology for
early-stage drug discovery and development [19-20]. This
strategy consists of screening low molecular weight
compounds (pharmacophores) against macromolecular
targets (usually proteins) of clinical relevance. Previously,
the “fragment-to-fragment” approach has been used for
studying interactions between oxazole and its derivatives
with aromatic acid residues in the protein molecule in
[Pharm-BioM] complexes formed on the basis of the
-stack interaction [21-23]. The oxazole cycle contains two-
coordinated nitrogen atom with a lone electron pair (LEP);
therefore, it can be considered as a donor center for the
formation of [Pharm-BioM] complex with amino acid
residues of proteins such as lysine, arginine and histidine by
the mechanism of hydrogen bonds interaction.
This paper presents the results of in-silico studies of the
stability of the [Pharmophore-Peptide] complex formed
between peptide moieties in a model protein and
heterocycles as pharmacophores using the “fragment-to
fragment” approach.
Materials and calculation method
It was found that oxazole derivatives demonstrated their
biological activity [24-26] associated with their ability to
form a stable [Pharm-BioM] complex. The oxazole mole-
cule has two distinctive features: 1) it contains a branched
-system, therefore, it can form a complex due to the
-stack interaction with suitable conjugated fragments of
biomolecules; 2) it contains the dicoordinated nitrogen atom
with the LEP and, therefore, can form the complex due to a
hydrogen bond when this atom is a proton acceptor. Then,
in this paper, the possible expansion of the conjugate
system and the increase the number of the LEPs in the
anellated compounds 1-4 were investigated. Of course, the
real pharmacophore molecules contain both the conjugated
and non-conjugated substituents. However, in this study,
only the heterocyclic moieties will be considered.
Regarding the polypeptide chain, only the model
molecules containing one and two peptide bonds are studied
(Table 1, structures 5 and 6).
The double bond of the >C=O group and the LEP of the
nitrogen atom form a short conjugated system, while the
LEPs of the oxygen atom could take part in the formation of
hydrogen bonds with hydrogen atoms. So, here we will
consider only the complex of molecules 1-4 with model
molecules 5, 6 formed by the -stack interaction and
hydrogen bonds.
The main characteristics of the electron structure
(optimized molecular geometry, charge distribution,
energies and shapes of molecular orbitals) were calcu-
lated by DFT [wB97XD/6-31G(d.p.)] method (package
GAUSSIAN 03 [27]).
Results and Discussion
Possible interaction compounds 1-4 and its derivatives
with the peptide bonds
According to theoretical conception, the capacity of the
organic molecules to form stable complex with bio-
molecules is essential condition of the biological activity; it
is designated as its affinity or biological affinity [28-29].
Then, pharmacophore [Pharm] and biological molecule
Peptide [Pept] form the stable complex [Pharm-Pept]:
ISSN 1814-9758. Ukr. Bioorg. Acta, 2021, Vol. 16, N 1
36
The complex stability depends on the electronic
environment of both components. We supposed that the
complex and its component are neutral and hence no
electron redistribution between the components upon
complexation occurs [30]. Stabilization energy of the
complex (or binding energy Ebind) was estimated as the
difference of the total energies of the complex its
components:
Ebind = E[Complex] – E[Comp 1] – E[Comp 2] (1)
where E[Complex] is energy of the optimized complex, while
E[Comp 1] and E[Comp 2] are energies of both optimized
components.
Recently, the “fragment-to-fragment” approach was
proposed [22-23], which could be considered as the next
step in silico modeling. It divides the total interaction into
the particular components and hence enables estimating the
interaction energies between fragments by the more correct
non-empirical quantum-chemical methods, i.e. it taken into
consideration the chemical and electronic structures of the
complex and those of the both components.
In this paper, the so-called hydrophobic interaction is not
considered. It should also be noted that the formation of
conformational formations of the polypeptide chain is
accompanied by the stabilization of protein structures
through the formation of hydrogen bonds between
-NH•••O=C peptide fragments. In the helix, then, the
peptide bonds that form the protein conformation do not
interact effectively with the pharmacophore molecules.
Pharmacophores can form complexes only with “free”
peptide bonds of the untwisted part of the protein.
Generally, the stack interaction between two -electron
systems A (Pharmacophore) and B (Biomolecule) is
determined by the relative positions of the molecular levels
of both molecules, can be estimated by perturbation theory
[31], using the following equation (2):
(2)
where i and j are MO energies; Ci and Cj are MO
coefficients; nieces i, system A, while indices j,
system B; the first two sums run over all levels, whereas
second two sums run over all atoms (-centers).
Equation (2) implies that interactions between the
occupied levels of one component (Pharmacophore) with
the vacant levels of another component (Peptide) should be
effective, while interactions between the occupied levels or
vacant levels of both components should not be effective.
Of course, the interaction amplitude depends on the overlap
of the orbitals (or more exactly, on the coefficients Ci). The
molecular levels of the components will be discussed later.
Molecular characteristics of complex components
Planarity and geometrical dimensions of molecules
studied
Optimized structures of molecules 1-6 and correspon-
ding complexes are planar, what is typical for the
conjugated systems; this planarity is not disturbed upon
complexation. Molecular dimension of the complex
components are in the same order; they are presented in
Figure 1.
Figure 1. Optimized geometry of the compounds 1b, 2b, 4-6.
Azoles 1 and their derivatives 2-4 take the molecular
volume: the thickness of -electron shell is 3.4 Å; then the
estimated values for the oxazole cycle is [6х6х3,4] Å3; for
the anellated derivatives it is [7х8,5х3,4] Å3; for the
model peptide 5 it is [7х5х3,4] Å3; for the model
dipeptide 6 it is [11х7х3,4] Å3. The hetero-substitution
O S NH2 somewhat increases the molecular volume.
As it follows from Figure 1, molecules 1-4 can form the
binary [Pharm-Pept] complex by -stacking interaction
with only one -system of the peptide; the bicyclic
molecules 2-4 could form the complex with two -moieties
in dipeptide 6.
The Lone electron pair (LEP) and n-molecular
orbitals (MO) dicoordinated nitrogen atoms.
As the molecules 1-4 contain dicoordinated nitrogen
atoms, (their trtrtr2 electron configuration), then n-MOs
occurs in the electron shell beside -levels. The
corresponding LEPs can participate in hydrogen bonds; the
corresponding interaction energy depends on the
dispositions of the n-levels. For sake of illustration, the
E
A A
i
B B
j ji
ji CC
Y. S. Velihina, N. V. Obernikhina, S. G. Pilyo et al.
37
-14
-12
-10
-8
-6
-4
-2
0
2
4
E, eV
Fermi level
HOMO
LUMO
-2
0
5
-1
+1
6
0
-2
-3
-1
0
0
+1
a)
-12
-10
-8
-6
-4
-2
0
2
4
Fermi level
E, eV
HOMO
LUMO
b)
2b 2a 2c
0
0
+1
-1
-2
-14
-12
-10
-8
-6
-4
-2
0
2
4
Fermi level
E, eV
c)
HOMO
LUMO
2b 3 4 1b
0
0
-1
-2
-3
-4
+1
Figure 2. Shape of frontier MO and n-MO in the peptides 5-6 (a), compounds 2a-2c (b) and 1b, 2b, 3, 4 (c)
ISSN 1814-9758. Ukr. Bioorg. Acta, 2021, Vol. 16, N 1
38
energies and shapes of the frontier and nearest MOs in the
oxazole 1 and its anellated derivatives 2-4 as well as the
model peptide 5 and dipeptide 6 are pictured in Figure 2.
Elongation of the polypeptide chain (introduction of the
second peptide unit), as shown in Figure 2а, leads to an
asymmetric distribution of electron density in the dipeptide.
This distribution must be taken into account when
interacting with the pharmacophore by the -stack
mechanism. The n-molecular orbital (n-MO), which is
"responsible" for the formation of a hydrogen bond in
complex formation, as shown in Figure 2b, is not sensitive
to the replacement of the heteroatom X in compounds 2: it
remains HOMO-2, although it has slightly different energy
value, which was also shown earlier on monocyclic
5-membered heterocycles [23].
Expansion of the conjugation system of the studied
compounds 1a-1c due to anellation (1 2) leads to the
appearance of a new highly positioned -MO; therefore
n-MO is now HOMO-2. At the same time, the addition of
the pyridine acceptor cycle leads to the appearance of an
additional (pyridine) n-MO, which is much higher in energy
(HOMO-1), and the n-MO of the heterocycle shifts
downward (HOMO-3) (Figure 2c). Annelation by a more
pyrimidine acceptor cycle causes the appearance of another
additional n-MO, which occupies the HOMO position, and
a subsequent shift in energy of n-MO of the heterocycle
makes it HOMO-4 (Figure 2c). It should be noted that the
interaction of the additional n-MOs with each other is
accompanied by their splitting, which causes a greater shift
of the n-level to higher orbital energy. Besides, such a
change in the mutual position of the -levels and n-levels
should affect the stability of the [Pharm-Pept] complex
stabilized by hydrogen bonds.
Index 0 as a quantitative characteristic of donor-
acceptor properties
It was proposed earlier [32] to estimate quantitatively the
donor-acceptor properties of the conjugated molecules
analyzing positions of the frontier MOs relatively to the
non-bonding -level (so-called Fermi level of -electrons)
0; this parameter is calculated by equation (3):
0 = (LUMO - )/ (3)
where = LUMO - HOMO, LUMO is the energy of the
LUMO; HOMO is the energy of the HOMO; = -3.56 еV is
the energy of Fermi level (the middle of the HOMO-LUMO
gap for the polyene with 15 double bonds) [33].
If the energy gap is symmetrical relative to the virtual
level α, then φ0 = 0.5 and hence the donor and acceptor
properties are mutually balanced; the shift of the energy gap
up (and hence increase of the parameter φ0 > 0.5) indicates
a mainly donor nature of the conjugated molecule; on the
contrary, if φ0 < 0.5, then the frontier levels are shifted
down, evidencing a predominately acceptor nature [32]. The
calculated MO energies and parameter φ0 of molecules
studied 1-6 are collected in Table 2.
Table 2. MO energies and parameter φ0 of the compounds
1-2(a-c) and 5, 6.
Compd X εa, eV b 0
c
HOMO LUMO
5 -8.57 3.34 11.91 0.579
5 (cis) -8.72 2.97 11.69 0.558
6 -8.60 2.11 10.71 0.530
6 (cis) -8.60 2.12 10.72 0.530
1a NH -8.12 2.59 10.71 0.574
1b O -8.86 1.67 10.53 0.497
1c S -8.27 0.64 8.91 0.471
2a NH -8.05 1.34 9.39 0.522
2b O -8.54 0.88 9.42 0.471
2c S -8.42 0.79 9.21 0.472
Polyene-15d -6.21 -0.91 5.30 0.500
aε is energy of orbital;
b = (LUMO) - (HOMO);
c0 = [(LUMO) - ]/ [33]; = -3.56137 eV [33];
dsee [32].
Table 2 demonstrated that the model peptides 5 and 6
(as electron-excessive -systems) are donor molecules,
whereas compound 1 and anellated derivatives 2-4 are
acceptors. Also, one can see that expansion of the
-conjugated system by anellation decreases firstly the
LUMO energy, then parameter 0 decreases also regularly
in the series of the compounds 1-2-3-4. It can be assumed
that the interaction of peptides as donors should be more
efficient with heterocycles 2-4 as stronger acceptors.
[Pharm:Pept] Complex stabilized by stacking --inte-
raction
Going from heterocycles 1 to the anellated derivatives
2-4 and model peptides 5 and 6, one can see that the
formation of [Pharm-Pept 5] complex by the mechanism of
the -stack interaction should be more efficient for
compounds 1, and [Pharm-Pept 6] is more effective for
anellated derivatives 2-4.
The peptide bond =C(O)–NH– can exist in two
conformations (cis- and trans-) relative to the polypeptide
chain plane [34-35]. Two possible [Pharm-Pept 5]
complexes with the oxazole 1b were calculated. For other
molecules (1a and 1c), the complex was calculated with
peptide 5 in the trans-configuration. The binding energies
calculated for different complexes [Pharm-Pept 5] of
compounds 1 with the model peptide 5 are presented in
Table 3.
Stabilization energies of [1b-Pept 5 (cis-)] and [1b-Pept 5
(trans-)] complexes differ considerably: 3 kcal/mol; then
the complex with the cis-isomer is more stable. Also, our
modeling shows that the binding energy of the complex
[Pharm-Pept] is sensitive to the nature of heteroatom X;
going from the oxazole 1b (X = O) to imidazole 1a and
Y. S. Velihina, N. V. Obernikhina, S. G. Pilyo et al.
39
thiazole 1c increases the complex stability to 2 kcal/mol
and 10 kcal/mol respectively. However, there is no direct
correlation between stabilization energy and parameter 0;
it seems to be connected with the different energy gaps .
Table 3. The binding energies of -complexes of the
compounds 1a-c with model peptide 5.
Compd Emol
a, a.u. [Compound-Pept 5]
Ecompl
b,
a.u.
Ecompl
c,
a.u.
Ed,
kcal/mol
1b -245.992 - -494.458 -9.30
1b -245.992 -494.457 - -12.11
1a -226.147 - -474.616 -11.13
1c -568.951 - -817.434 -19.76
5 (trans-) -248.451
5 (cis-) -248.446
aEcompd is a total energy of compounds;
bEcompl is a total energy of [Compound-Pept 5]complex, where the
peptide bond is in the cis-position;
cEcompl is a total energy of [Compound-Pept 5]complex, where the
peptide bond is in the trans-position;
dE is a binding energy, calculated by equation (1).
Now, let us estimate the effect of expansion of the
conjugated system oxazole and its derivatives during
anellation. Firstly, it should be noted that bicyclic molecules
2-4 have a common plane of overlap with both peptide 5
and dipeptide 6. For sake of illustration, Figure 3 shows the
optimized geometries of the complexes of the benzoxazole
2b with the model molecules 5 and 6:
(a)
(a)
(b) (b)
Figure 3. Mutual arrangement of both components in
--complex [Pharm-Pept]: a) compound 2b with model peptide 5
residue in X-Y plane and X-Z plane; b) compound 2b with model
dipeptide 6 residue in X-Y plane and X-Z plane.
As indicated in Table 2 and Figure 2b, anellation is
accompanied by the convergence of the frontier levels. This
should increase the energy interaction between the vacant
levels of the pharmacophore and occupied levels of the
model peptide molecule according to equation (2). The
same conclusion concerns the interaction between the
occupied levels of the pharmacophore and vacant levels of
the model peptide molecule. Hence, the stability of
[Pharm-Pept] -complex upon anellation should increases.
The calculated binding energies in the complexes of the
anellated molecules 2-4 with the model peptide 5 and
dipeptide 6 are collected in Table 4.
Table 4. The binding energies of -complexes of the compounds 2b, 3 and 4 with model peptides 5 and 6.
Compd anellation Emol
a, a.u. [Compound-Pept 5] [Compound-Pept 6]
Ecompl
b, a.u. Ec,
kcal/mol
Ecompl, a.u. E,
kcal/mol
2b Benzene -399.586298485 -648.060865334 -14.48 -856.02241454 -30.60
3 Pyridine -415.62782517 -664.09305761 -8.63 -872.056904788 -26.19
4 Pyrimidine -431.65161043 -680.1122263 -5.73 -888.07587177 -23.16
peptide 5 -248.451486374
peptide 6 -456.387350963
aEcompd is total energy of compounds;
bEcompl is total energy of [Compound-Pept] complex;
cE is a binding energy, calculated by equation (1).
Comparing Tables 3 and 4 shows that anellation of the
compounds 1 leads to sensible increasing of the binding
energies. Going to the possible complex with the dipeptide
6 (with two parallel peptide conjugated systems) increases
twofold the stabilization energy.
At the same time, the data in Table 4 point that replacing
of methine groups in benzene ring by the more
electronegative nitrogen atoms decreases the highest
occupied level of pharmacophore and hence it holds away
from the vacant level of the peptide; hence the stabilization
energy decreases in the series of the compounds 234.
ISSN 1814-9758. Ukr. Bioorg. Acta, 2021, Vol. 16, N 1
40
Complex stabilized by hydrogen bonds
Another type of the stable [Pharm-BioM] complexes is
formed by generation of the hydrogen bonds between the
components (further: [HB]-complex). In this complex the
nitrogen atoms with LEP are considered as acceptor centers
of such hydrogen bonds. Also, the molecules studied can
form hydrogen bonds with some amino acids in proteins
containing the functional groups -NH2, -OH, -SH. For sake
of comparison, the possible complex with model amino
acid residues are H3C-Y-H, were Y = NH, O, S; the non-
conjugated fragment in amino acids was modeled by methyl
group. Therefore, the various conformation will not taken
into consideration: we optimistically suppose that we can
neglect different conformations. Besides, we will compare
stabilization energies of [HB]-complexes in the series of
structurally similar compounds. Before the optimization
procedure, complex components were disposed at the
distance of 2.1 Å; Y-H bond was in the plane, whereas the
component planes in the complex were disposed
perpendicularly. For molecules 3-4 containing 2 or 3
nitrogen atoms (Figure 4) all possible isomeric complexes
were calculated.
Figure 4. Possible options for creating a [HB]-complex by the
mechanism of hydrogen bonding for compound 4.
It is assumed that the energy and length of the hydrogen
bond in the [HB]-complex depend on charge on the
nitrogen atom; then the stability of such an isomeric [HB]-
complex should be different.
First of all, the [HB]-complex of the simplest molecules
1, 2 with model functional amino acid residues will be
considered in order to study the dependence of the [HB]-
complex stability on chemical composition of the model
functional molecule H3C-Y-H. The calculated binding
energies are presented in Table 5.
Table 5 shows that the nitrogen atom of compounds 1-2
has a relatively large negative charge, its value depends on
the nature of the heteroatom X. When compounds 1 are
annelated, the charge on the nitrogen atom increases, also
depending on the nature of the heteroatom X. This charge
sensitivity should affect the stability of the [HB]-complex.
Variation of the functional residues in the model
molecule H3C-Y-H shows that the most stable [HB]-
complex of compounds 1 is formed with OH-group; a
similar tendency is observed for a number of
benzoanalogues 2, anellation of the compounds 1 increases
the binding energy.
Replacing of the heteroatom also is accompanied by the
[HB]-complex stability, though anellated benzothiazole 2c
(X = S) is considerably less stable, which seems to be
connected with a high energy of the n-MO that is the LEP
on the sulfur atom. Additionally, the H•••S- hydrogen bond
is somewhat lengthened.
Going from the simplest oxazole 1 to its derivatives 3
and 4 anellated by the pyridine or pyrimidine, two or even
three types of the [HB]-complexes could be formed by the
hydrogen bond, as shown in Figure 4. The binding energies
calculated for all possible [HB]-complexes with the model
molecule H3C-O-H are presented in Table 6.
Firstly, negative charge at the nitrogen atom (1) is
weakly sensitive on the change of the benzene ring to
pyridine and pyrimidine cycles. Going from the molecule
2b to its nitrogen analogue 3 decreases slightly the binding
energy of the [HB]-complex formed via hydrogen bonding
with the nitrogen atom in 5-membered oxazole cycle. In the
same time, for derivative 4, annelated by the pyrimidine
cycle, the stabilization energy 4 kcal/mol was predicted
by calcularions. The analyses of both possible [HB]-
complexes with molecule 3 shows that the forming of the
[HB]-complex with the nitrogen atoms (2) and (3) is less
stable ( 1.8 kcal/mol). One can also see that all three
isomeric complexes with the molecule 4 are appreciably
stable. Besides, the Table 5 demonstrates that these isomers
differ sizeable between them, the [HB]-complex bonded by
the hydrogen bond with the nitrogen atom (1) is most
stable.
Finally, let us consider the [HB]-complexes of peptide
molecules 5 as hydrogen-bonded complexes with the N-H
proton donors. The calculated data are collected in Table 7.
Y. S. Velihina, N. V. Obernikhina, S. G. Pilyo et al.
41
Table 5. Hydrogen bond energy values for the complexes [Compound-H-X] involving compounds 1-2(a-c) with H3C-Y-H.
Complex H-X za, e.u. Lb, Å Ecompd
c, a.u. Ecompl
d, a.u. Ee,
kcal/mol
[compound 1b-HX] H2N-CH3 -0.430 2.434 -245.99202 -341.83384 -7.92
[compound 1b-H-X] H-O-CH3 -0.430 1.949 -245.99202 -361.69005 -8.22
[compound 1b-H-X] H-S-CH3 -0.430 2.283 -245.99202 -684.670094 -6.57
[compound 1a-H-X] H-O-CH3 -0.449 1.922 -226.14680 -341.84861 -10.59
[compound 1c-H-X] H-O-CH3 -0.359 1.973 -568.95108 -684.67167 -22.37
[compound 2b-H-X] H2N-CH3 -0.474 2.503 -399.59471 -495.43508 -7.02
[compound 2b-H-X] H-O-CH3 -0.474 1.978 -399.59471 -515.295092 -9.69
[compound 2b-H-X] H-S-CH3 -0.474 2.454 -399.59471 -838.275012 -7.96
[compound 2a-H-X] H-O-CH3 -0.500 1.943 -379.74776 -495.45252 -12.44
[compound 2c-H-X] H-O-CH3 -0.417 1.959 -722.57396 -838.27227 -8.40
H-O-CH3 -115.684935 - -
H2N-CH3 -95.8292016 - -
H-S-CH3 -438.667606 - -
az, e.u. is the charge on the nitrogen atom, electronic units;
bl is the length of the hydrogen bond;
cEcompd is the energy of the compounds;
dEcompl is the energy of the [Compound-H-X] complex;
eE is the stabilization energy complex, calculated by formula (1).
Table 6. Hydrogen bond energy values for the complexes [Compound-H-X] involving compounds 2b, 3-4 with H3C-O-H.
Complex Na zb, e.u. lc, Å Ecompd
d, a.u. Ecompl
e, a.u. Ef,
kcal/mol
[compound 2b-H-X] 1 -0.474 1.978 -399.59471 -515.29509 -9.69
[compound 3-H-X] 1 -0.478 2.022 -415.62783 -531.32932 -10.39
[compound 3-H-X] 2 -0.497 1.993 -415.62783 -531.32648 -8.61
[compound 4-H-X] 1 -0.441 2.055 -431.65161 -547.35840 -13.71
[compound 4-H-X] 2 0.458 2.028 -431.65161 -547.35444 -11.23
[compound 4-H-X] 3 0.431 2.000 -431.65161 -547.35725 -12.99
H-O-CH3 -115.68494 - -
aN - position of the nitrogen atom in the anellated cycle of a substance (according to Figure 4);
bz, e.u. is the charge on the nitrogen atom, electronic units;
cl is the length of the hydrogen bond;
dEcompd is the energy of the compounds;
eEcompl is the energy of the [Compound-H-X] complex;
fE is the stabilization energy complex, calculated by formula (1).
Comparing Tables 6 and 7 shows similar tendencies
obtained for the [Compound-Pept 5] with both model
peptide 5 and model molecule H3C-OH. However, in
contrast to H3C-OH, the energy of hydrogen bonding with
the nitrogen atom (1) for compound 4 is lower than that
with the nitrogen atoms (2) and (3). It can be conclude that
the [Compound 3-Pept 5] and [Compound 4-Pept 5]
complexes formed with the peptide moieties of the
untwisted part of the protein at the nitrogen atoms of the
pyridine type are more stable.
It is to noticed that the some [Compound-Pept 5] could
be simultaneously formed for the molecules 3 and 4 with
two or even three hydrogen bonds. This should additionally
stabilize the [Pharm-Pept] complex.
ISSN 1814-9758. Ukr. Bioorg. Acta, 2021, Vol. 16, N 1
42
Table 7. Stabilization energies for [Compound-Pept 5]
complexes of molecules 1-4 with model peptide 5.
Complex Na Ecompd
b,
a.u.
Ecompl
c,
a.u.
Ed,
kcal/mol
[compound 1b-Pept 5] 1 -245.992 -494.46044 -10.63
[compound 2b-Pept 5] 1 -399.595 -648.06555 -12.14
[compound 3-Pept 5] 1 -415.628 -664.09780 -11.73
[compound 3-Pept 5] 2 -415.628 -664.09637 -10.70
[compound 4-Pept 5] 1 -431.652 -680.11718 -8.84
[compound 4-Pept 5] 2 -431.652 -680.11929 -10.16
[compound 4-Pept 5] 3 -431.652 -680.11929 -10.15
Peptide 5 -248.452
aN - position of the nitrogen atom in the anellated cycle of a substance
(according to Figure 4);
bEcompd is the energy of the compounds;
cEcompl is the energy of the [Compound-Pept 5] complex;
dE is the stabilization energy complex, calculated by formula (1).
Conclusions
In silico the theoretical analysis of the interaction
between pharmacophore molecules based on bicyclic
nitrogen heterocycles with model peptides shows that the
stabilization of [Pharm-Pept] complexes is ensured by the
-stack interaction of the pharmacophore molecule systems
with the -peptide bond system. The expansion of the
conjugate heterocyclic compounds by anellation is
accompanied by an increase in the acceptor properties of
studied heterocycles, stabilizing the [Pharm-Pept]
complexes formed by the -stacking interaction mechanism
increases. Elongation of the polypeptide chain increases
significantly the stabilization energy of the [Pharm-Pept]
complexes.
In the formation of complexes by the mechanism of
hydrogen bonds between the LEP of the dicoordinated
nitrogen atom and the functional groups of amino acids -
OH, -NH2, -SH the most stable [HB]-complexes was found
for OH-group, the least stable [HB]-complexes was
predicted for SH-group. The expansion of the conjugated
anellated system is accompanied by an increase in the
acceptor properties of nitrogen containing heterocycle as
pharmacophores, especially during anellated with pyridine
and pyrimidine, which leads to increased stability of the
complexes formed by the hydrogen bonding mechanism.
The transition to bicyclic conjugate systems with two or
three dicoordinated nitrogen atoms provides additional
stabilization of [Pharm-BioM] complexes due to the
possible simultaneous formation of several hydrogen bonds.
The stabilization energy of [HB]-complexes for compounds
2b and 3 with a “free” peptide bond of the extended part of
the protein is slightly lower compared to the functional
OH-group of amino acids, and for compound 4, on the
contrary, 2 kcal/mol higher. Compound 4 is likely to show
more pronounced properties in further in vitro studies.
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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In silico дослідження взаємодії гетероциклічних основ з пептидними групами
білків: пофрагментний підхід
Є. С. Велігіна1, Н. В. Оберніхіна2*, С. Г. Пільо2, М. В. Качаєва2, О. Д. Качковський2
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 модельних пептидів (Пепт) та
гетероциклічних основ, конденсованих з піридином та піримідином, як фармакофорів (Фарм). Скрупульозний аналіз даних показує, що
розширення кон'югованих гетероциклічних сполук за допомогою анелювання супроводжується збільшенням акцепторних властивостей
досліджуваних гетероциклів, в результаті чого стабільність комплексів [Фарм-Пепт], утворених за механізмом -стекової взаємодії
збільшується. При подовженні поліпептидного ланцюга спостерігається вдвічі збільшення енергії стабілізації комплексів [Фарм-Пепт]. При
утворенні комплексів [Фармакофор-Біомолекула] між спряженими гетероциклічними основами з двома-трьома дикоординованими атомами
азоту та функціональними групами амінокислот (-OH, -NH2, -SH) за механізмом водневих зв’язків виявились найбільш стабільними комплекси з
OH-групою. Розширення спряженої системи досліджуваних гетероциклів шляхом анелювання з піридином та піримідином призводить до
підвищеної стабільності комплексів. Енергія комплексоутворення для сполук 2b та 3 із «вільним» пептидним зв’язком розгорнутої частини білка
дещо нижча порівняно з енергією комплексів досліджуваних сполук з ОН-групою амінокислот, а для сполуки 4, навпаки, енергія на 2 ккал/моль
вище. Сполука 4, ймовірно, проявлятиме більш виражені властивості в подальших дослідженнях in vitro.
Ключові слова: підхід «фрагмент до фрагмента»; пептидні зв’язки; афінність зв’язування; комплекс [Фармакофор-Біомолекула]; -стекінгова
взаємодія; водневі зв’язки.
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7040036/
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https://onlinelibrary.wiley.com/action/doSearch?ContribAuthorStored=Kachkovsky%2C+Oleksiy+D
https://onlinelibrary.wiley.com/action/doSearch?ContribAuthorStored=Brovarets%2C+Volodymyr+S
http://www.dopovidi-nanu.org.ua/en/search?f%5Bauthor%5D=5866
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http://www.dopovidi-nanu.org.ua/en/search?f%5Bauthor%5D=436
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| id | oai:ojs2.bioorganica.com.ua:article-46 |
| institution | Ukrainica Bioorganica Acta |
| keywords_txt_mv | keywords |
| language | English |
| last_indexed | 2026-07-20T01:01:01Z |
| publishDate | 2021 |
| 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/9e/f72bdf0b65f9a82f6b886fe7cec2ad9e.pdf |
| spelling | oai:ojs2.bioorganica.com.ua:article-462026-07-19T14:56:54Z In silico study the interaction of heterocyclic bases with peptide moieties of proteins in “fragment-to-fragment” approach In silico дослідження взаємодії гетероциклічних основ з пептидними групами білків: пофрагментний підхід Velihina, Yevheniia S. Obernikhina, Nataliya V. Pilyo, Stepan G. Kachaeva, Maryna V. Kachkovsky, Oleksiy D. fragment-to-fragment approach peptide bond biological affinity [Pharm-BioM] complex п-stacking interaction hydrogen bonding підхід «фрагмент до фрагмента» пептидні зв’язки афінність зв’язування комплекс [Фармакофор-Біомолекула] п-стекінгова взаємодія водневі зв’язки The binding affinity of model peptide moieties (Pept) and heterocyclic bases involving 1,3-oxazoles that are condensed with pyridine and pyrimidine as pharmacophores (Pharm) was investigated in silico and analyzed within the “fragment-to-fragment” approach. The anellation of the heterocyclic rings increasing their acceptor properties is accompanied by gaining stability of the [Pharm-Pept] complexes formed by the p-stack interaction. It was found that elongation of the polypeptide chain led to a twofold increase of the stabilization energy of the [Pharm-Pept] complexes. The stability of the hydrogen bonding ([HB]) [Pharm-BioM] complexes formed by means of the interaction between the dicoordinated nitrogen atom of the heterocycle and the functional groups of peptide amino acids (-OH, -NH2, -SH) was evaluated. It was demonstrated that [HB]-complexes that were formed by hydrogen bonds formation with amino acid that contained OH groups had the largest stabilization effect. The anellation with pyridine and pyrimidine rings led to stability increase of the complexes formed by the hydrogen bonding mechanism. The binding energy of [HB]-complexes for compounds 2b and 3 with a "free" peptide bond of the extended part of the protein is lower compared to amino acids with OH-functional groups. On the contrary, the binding energy of compound 4 with peptides was 2 kcal/mol higher. Compound 4 demonstrated the most pronounced biological activity in vitro studies. В рамках підходу «фрагмент до фрагменту» представлені іn silico результати біологічної спорідненості модельних пептидів (Пепт) та гетероциклічних основ, конденсованих з піридином та піримідином, як фармакофорів (Фарм). Скрупульозний аналіз даних показує, що розширення кон'югованих гетероциклічних сполук за допомогою анелювання супроводжується збільшенням акцепторних властивостей досліджуваних гетероциклів, в результаті чого стабільність комплексів [Фарм-Пепт], утворених за механізмом p-стекової взаємодії збільшується. При подовженні поліпептидного ланцюга спостерігається вдвічі збільшення енергії стабілізації комплексів [Фарм-Пепт]. При утворенні комплексів [Фармакофор-Біомолекула] між спряженими гетероциклічними основами з двома-трьома дикоординованими атомами азоту та функціональними групами амінокислот (-OH, -NH2, -SH) за механізмом водневих зв’язків виявились найбільш стабільними комплекси з OH-групою. Розширення спряженої системи досліджуваних гетероциклів шляхом анелювання з піридином та піримідином призводить до підвищеної стабільності комплексів. Енергія комплексоутворення для сполук 2b та 3 із «вільним» пептидним зв’язком розгорнутої частини білка дещо нижча порівняно з енергією комплексів досліджуваних сполук з ОН-групою амінокислот, а для сполуки 4, навпаки, енергія на 2 ккал/моль вище. Сполука 4, ймовірно, проявлятиме більш виражені властивості в подальших дослідженнях in vitro. V.P. Kukhar Institute of Bioorganic Chemistry and Petrochemistry of the National Academy of Sciences of Ukraine 2021-06-30 Article Article application/pdf https://bioorganica.com.ua/index.php/journal/article/view/46 10.15407/bioorganica2021.01.034 Ukrainica Bioorganica Acta; Vol. 16 No. 1 (2021): Ukrainica Bioorganica Acta; 34-43 Ukrainica Bioorganica Acta; Том 16 № 1 (2021): Ukrainica Bioorganica Acta; 34-43 1814-9766 1814-9758 10.15407/bioorganica2021.01 en https://bioorganica.com.ua/index.php/journal/article/view/46/46 Copyright (c) 2021 Yevheniia S. Velihina, Nataliya V. Obernikhina, Stepan G. Pilyo, Maryna V. Kachaeva, Oleksiy D. Kachkovsky https://creativecommons.org/licenses/by/4.0 |
| spellingShingle | підхід «фрагмент до фрагмента» пептидні зв’язки 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. In silico дослідження взаємодії гетероциклічних основ з пептидними групами білків: пофрагментний підхід |
| title | In silico дослідження взаємодії гетероциклічних основ з пептидними групами білків: пофрагментний підхід |
| title_alt | In silico study the interaction of heterocyclic bases with peptide moieties of proteins in “fragment-to-fragment” approach |
| title_full | In silico дослідження взаємодії гетероциклічних основ з пептидними групами білків: пофрагментний підхід |
| title_fullStr | In silico дослідження взаємодії гетероциклічних основ з пептидними групами білків: пофрагментний підхід |
| title_full_unstemmed | In silico дослідження взаємодії гетероциклічних основ з пептидними групами білків: пофрагментний підхід |
| title_short | In silico дослідження взаємодії гетероциклічних основ з пептидними групами білків: пофрагментний підхід |
| title_sort | in silico дослідження взаємодії гетероциклічних основ з пептидними групами білків: пофрагментний підхід |
| topic | підхід «фрагмент до фрагмента» пептидні зв’язки афінність зв’язування комплекс [Фармакофор-Біомолекула] п-стекінгова взаємодія водневі зв’язки |
| topic_facet | fragment-to-fragment approach peptide bond biological affinity [Pharm-BioM] complex п-stacking interaction hydrogen bonding підхід «фрагмент до фрагмента» пептидні зв’язки афінність зв’язування комплекс [Фармакофор-Біомолекула] п-стекінгова взаємодія водневі зв’язки |
| url | https://bioorganica.com.ua/index.php/journal/article/view/46 |
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