Turkish Computational and Theoretical Chemistry

Turkish Comp Theo Chem (TC&TC)

Volume(Issue): 9(1) – Year: 2025 – Pages: 63-74

e-ISSN: 2602-3237
https://doi.org/10.33435/tcandtc.1500969
Received: 22.06.2024 Accepted: 16.07.2024 Research Article
An insilico study of new 1-aminoquinoline-2(1H)-one derivatives as tyrosine kinase inhibitors

Sarah Sattar Jabbar1, Mohammed Hassan Mohammed

Department of Pharmaceutical Chemistry, College of Pharmacy, University of Baghdad/Iraq

Abstract: The field of oncology has been revolutionized by the discovery and development of targeted
therapies for cancer. Although tyrosine kinase inhibitors (TKIs) have shown promise in targeting cancer cell
signaling pathways, the emergence of resistance necessitates the development of novel and potent inhibitors.
This study explores the design and evaluation of two series of 1-aminoquinoline-2(1H)-one derivatives as
potential TKIs. Virtual docking simulations, which use molecular docking algorithms and scoring functions,
predict how these TKIs bind to the enzyme and assess their binding strength. The Molecular Operating
Environment (MOE) software version 2015.10 was used to carry out these molecular docking simulations.
Using the X-ray crystal structure of the Abelson tyrosine kinase (ABL1) from the Protein Data Bank (PDB
ID: 4WKQ), the binding interactions and efficacy of the newly designed TKIs were evaluated. Preliminary
results show that several of the designed TKIs have a strong binding affinity and form key interactions with
the target tyrosine kinase. These interactions include hydrogen bonds, hydrophobic interactions, and
electrostatic interactions, which are crucial for stabilizing the complex between the TKI and the enzyme.
Additionally, the study identifies specific amino acid residues within the tyrosine kinase binding site that
enhance the binding affinity of the TKIs. This detailed information is valuable for further optimizing TKI
design and developing more effective inhibitors with improved binding properties.

Keywords: Tyrosine kinase inhibitors (TKIs), Targeted therapy, Virtual docking simulations, 1-
aminoquinoline-2(1H)-one derivatives.

1. Introduction of TK inhibitors exist, distinguished by their

Tyrosine kinases are enzymes responsible for mechanisms of action and selectivity, ATP-
transferring phosphate groups from ATP to tyrosine competitive inhibitors [6]: These inhibitors bind to
residues on specific proteins thereby regulating the ATP binding site of the tyrosine kinase enzyme,
different cellular functions[1]. In the context of hindering ATP binding along with as a result
cancer cells, the defective activation of tyrosine hindering kinase activity, Imatinib with Dasatinib
kinases can lead to unregulated cell proliferation are the available medicines of ATP-competitive
and survival[2]. Tyrosine kinase inhibitors (TKIs) inhibitors used for treating different cancers like
are a class of medications designed to specifically chronic myeloid leukemia as well as specific solid
target and suppress the activity of tyrosine kinase tumors [7-8]. Allosteric inhibitors: These inhibitors
and emerged as crucial therapeutics in cancer attach to a distinctive site on the kinase enzyme,
treatment[3], as well their applications extend different from the ATP binding site, by causing a
beyond oncology to encompass other disease areas conformational modification they prevent kinase
like autoimmune disorders and infectious activity [9-10], Gefitinib and erlotinib (non-small
diseases[4]. cell lung cancer cells) are instances of allosteric
TK inhibitors offer diverse strategies to target inhibitors and Covalent inhibitors: These inhibitors
tyrosine kinases and modulate their activity for create a covalent bond with the tyrosine kinase
therapeutic purposes [5]. There are different types enzyme, causing permanent restraint of its activity,

1
Corresponding Authors
e-mail: [email protected]
 Turkish Comp Theo Chem (TC&TC), 9(1), (2025), 63-74

Sarah Sattar Jabba, Mohammed Hassan Mohammed

Afatinib as well as neratinib epitomize covalent development of these drugs entails a

inhibitors [11-12]. comprehensive understanding of the molecular
The field of TK inhibitors is continuously mechanisms involved in tyrosine kinase signaling,
progressing, with ongoing efforts to develop and as well as expertise in medicinal chemistry, drug
evaluate new compounds for their effectiveness and design, and rigorous preclinical and clinical testing
safety in treating various cancer types[13]. The [14].

Gefitinib Erlotinib

Afatinib Neratinib

Figure 1. Different types of TK inhibitors.

Despite the promising potential of TK inhibitors as Furthermore, TK inhibitors might exhibit off-target
effective anticancer agents, they do possess certain impacts causing unfavorable adverse effects like
limitations[15]. One significant restriction is the gastrointestinal disturbances, fatigue, and skin rash
emergence of drug resistance which can emerge [17]. These restrictions highlight the demand for
from mutations in the tyrosine kinase enzyme or the more research study and development to get over
activation of different signaling pathways. This resistance and reduce off-target impacts to enhance
resistance can diminish the effectiveness of TK the therapeutic potential of TK inhibitors[4,18].
inhibitors in targeting cancer cells[16].

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Sarah Sattar Jabba, Mohammed Hassan Mohammed

Designing new tyrosine kinase inhibitors (TKIs) and erlotinib, highlighting the potential of this
with improved efficiency as well as selectivity is scaffold in drug development[23]. Because the
important in targeted cancer treatment[19-20]. It synthesis of 1-aminoquinoline-2(1H)-one
facilitates the overcoming of resistance, enhances derivatives is well-established, these molecules
the potency of inhibition, permits efficient may be produced and optimized efficiently in
combination therapies, and broadens the range of Figure 2. This chemical accessibility makes the
cancer types for which treatment choices are rapid exploration of structure-activity
available[7,21]. These advancements support the relationships[24]. Considering the critical role that
development of precision medicine in the treatment tyrosine kinases play in disease, the development of
of cancer as well as better patient outcomes. novel inhibitors with distinct scaffolds, such as 1-
Quinoline derivatives have shown strong biological aminoquinoline-2(1H)-one, may result in novel
activity against a range of targets, including therapies with improved safety and effectiveness
kinases. Tyrosine kinases' ATP-binding site can profiles.
interact with the amino group at the 1-position and The docking studies will be carried out to estimate
the ketone at the 2-position, possibly resulting in the potential inhibition of a two series of derivatives
effective inhibition[22]. Quinoline compounds of 1-aminoquinoline-2(1H)-one as protein kinase
have been effectively used as kinase inhibitors in inhibitors against the Abelson tyrosine kinase
the past. Quinoline moieties are included in several (ABL1).
FDA-approved medications, including lapatinib
R1 R1

R2 R2

HN O HN O

H H
N N O N N O
N N

a b
O

Figure 2. Chemical Structures of Two Series of 1-Aminoquinoline-2(1H)-one Derivatives

The primary goal of the study was to investigate the 2. Computational Method
binding interactions, evaluate the effectiveness and The in silico docking technique is a computational
strength of a newly designed tyrosine kinase technique made use of to forecast exactly how a
inhibitor (TKI) against the Abelson tyrosine kinase small molecule, such as a tyrosine kinase inhibitor
(ABL1). ABL1 is a non-receptor tyrosine kinase (TKI), binds to a target protein such as a tyrosine
that plays a critical duty in cellular signaling kinase [28]. The research study executed molecular
pathways with cell growth, proliferation, and docking simulations utilizing the Molecular
survival [25-26]. The BCR-ABL1 fusion protein, Operating Environment (MOE) software
which is an abnormal form of ABL1, it is linked in application variation 2015.10 (Chemical
different cancer kinds involving chronic myeloid Computing Group, Montreal, Canada) [29] to
leukemia (CML) along with specific types of acute analyze the binding interactions, assess the
lymphoblastic leukemia (ALL)[20]. Targeting effectiveness and strength of a newly designed TKI
ABL1 with specific inhibitors, such as imatinib has against the Abelson tyrosine kinase (ABL1), the X-
significantly improved the management of CML by ray crystal structures of Abelson tyrosine kinase
inhibiting the activity of the BCR-ABL1 found in was acquired from the Protein Data Bank with the
CML [20]. This study evaluated the newly PDB ID (4WKQ) [30]. The final compounds were
developed TKIs potential as a treatment option for constructed using the MOE builder module and
malignancies linked to ABL1 by comparing it with energy minimized using the Merck Molecular force
established inhibitors (imatinib) [27]. field (MMFF94x, RMSD gradient: 0.05 kcal mol-
1 -1
Å ) [31]. The binding site of target protein was
determined using MOE Site finder, and docking
dummies were created [32]. The optimized

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Sarah Sattar Jabba, Mohammed Hassan Mohammed

geometry of the compound was then docked into Docking Analysis Results including the binding
the binding site using the MOE-Dock program. The affinity score, and key interacting residues as well
initial scoring method used was the London dG, Visualize the binding mode of the TKI within the
while the final scoring method was Rigid Receptor active site of the tyrosine kinase through molecular
[33]. graphics and analyze the obtained results and draw
conclusions regarding the potential effectiveness of
3. Results and discussion the newly designed TKI.
The research study intended to improve the TKIs
binding affinity along with selectivity for ABL1.

No. R1 R2 Energy of Binding Hydrogen bonds Non-H-bond interaction

(Kcal/mol)
a1 CH3 H -7.9 Non pi-H, LEU 718
a2 OCH3 H -7.1 MET 793 (3.27 Å), Non
LYS 745 (2.99 Å)
a3 F H -6.8 MET 793 (3.48 Å) LEU 718 (4.28), pi-H

a4 Cl H -6.7 MET 793 (3.62) Non

a5 CN H -7.1 MET 793 (3.17), GLY 796 (3.37A) pi-H
LYS 745 (3.25)
a6 CH2=CH2 H -8.3 Non LEU 718 (4.12A) pi-H
a7 CH3 F -8.1 LYS 745 (2.83A) Non
a8 CH3 CH3 -8.3 LYS 745 (2.96A) LYS 745 (4.01A) pi-cation
a9 CH3 Cl -7.1 LYS 745 (3.28A) Non
a10 CH3 OCH3 -7.7 MET 766 (4.17A) LEU 718 (4.17A) pi-H
a11 CH3 CN -7.6 Non LEU 718 (3.78A) pi-H
a12 CH3 CH2=CH2 -7.5 CSO 797 (3.16A), Non
MET 766 (3.88A),
LYS 745 (2.87 A)
a13 F F -7.1 MET 766 (3.15A) Non
a14 CH3 CH3 -7.2 Non LEU 718 (4.23A) pi-H
a15 Cl Cl -7.6 MET 793 (3.30A) LEU 718 (4.02A) pi-H,
LEU 718 (3.81A) pi-H
a16 OCH3 OCH3 -7.0 MET 793 (3.32A) Non
a17 CN CN -6.9 Non Non
a18 CH2=CH2 CH2=CH2 -7.1 THR 854 (3.06A), LYS 745 (4.21A) pi-cation
ASP 855 (2.83A),
LYS 745 (2.85A)
a19 Cl F -7.5 GLU 762 (3.04A) LEU 718 (4.27A) pi-H
a20 Cl CH3 -8.1 LYS 745 (3.28A) Non
a21 Cl Cl -8.2 GLU 762 (3.03 A) LEU 718 (4.29 A) pi-H
a22 Cl OCH3 -7.2 LYS 745 (3.44A) LEU 718 (3.83A) pi-H
a23 Cl CN -8.4 LYS 745 (3.44 A) LEU 718 (3.83A) pi-H
a24 Cl CH2=CH2 -7.5 MET 766 (3.34 A) Non
a25 OCH3 F -7.2 Non LEU 718 (3.70A) pi-H
a26 OCH3 CH3 -7.4 MET 793 (3.26A) LEU 718 (4.30A) pi-H,
GLY 796 (3.59 A) pi-H
a27 OCH3 Cl -7.3 LYS 745 (3.05A) Non
a28 OCH3 OCH3 -7.8 MET 793 (3.09A), GLY 796 (3.49A) pi-H
LYS 745 (3.04 A)
a29 OCH3 CN -7.4 Non Non
a30 OCH3 CH2=CH2 -7.3 LYS 745 (3.00A) LEU 718 (3.86A) pi-H
a31 CN F -7.7 PHE 856 (3.35A) VAL 726 (4.40A) pi-H
a32 CN CH3 -8.0 LYS 745 (2.93 A) LEU 718 (4.37 A) pi-H

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Sarah Sattar Jabba, Mohammed Hassan Mohammed

a33 CN Cl -7.2 MET 793 (3.34A), LEU 718 (4.01 A) pi-H,

LYS 745 (3.33A) LEU 718 (3.99 A) pi-H,
GLY 796 (3.48A) pi-H
a34 CN OCH3 -8.5 MET 793 (3.15A) GLY 796 (3.35A) pi-H
a35 CN CN -8.7 Non LYS 745 (3.77A) pi-cation
a36 CN CH2=CH2 -7.5 Non LEU 718 (4.09A) pi-H
a37 CH2=CH2 F -7.8 THR 854 (3.00 A) Non
a38 CH2=CH2 CH3 -6.8 MET 793 (3.20 A) GLY 796 (3.36 A) pi-H
a39 CH2=CH2 Cl -7.7 MET 793 (3.24A) GLY 796 (3.35A) pi-H
a40 OCH3 -7.3 MET 766 (3.05A) LEU 718 (3.69A) pi-H
a41 CH2=CH2 CN -7.3 LEU 788 (3.30A) Non
a42 CH2=CH2 CH2=CH2 -7.0 MET 793 (3.19A) LEU 718 (3.94 A) pi-H
GLY 796 (3.47A) pi-H
Imatinib -8.3 Non LYS 745 (3.58A) pi-cation

a6 a7

a8
a20

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Sarah Sattar Jabba, Mohammed Hassan Mohammed

a21
a23

a32 a34

a35 Imatinib
Scheme 1. 2D hematic diagram illustrating the target compound's docking model (for
the best compound) with the target 4WKQ protein.

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Sarah Sattar Jabba, Mohammed Hassan Mohammed

Table 2. Structure and Docking results of tyrosine kinase inhibitor-series (b) (compounds b1-b42)
and Imatinib against selected 4WKQ protein.
No. R1 R2 Energy of Binding Hydrogen bonds Non-H-bond interaction
(Kcal/mol)
b1 CH3 H -7.5 LEU 718 (3.59A) LEU 718 (3.79A) pi-H
CSO 797 (3.16A) LEU 718 (3.57A) pi-H
b2 OCH3 H -7.4 LEU 718 (3.21A) LEU 718 (4.43A) pi-
LEU 718 (3.89A) pi-H
b3 F H -6.9 Non LYS 745 (4.06A) pi-H
b4 Cl H -7.0 CSO 797 3.11A) Non
ASP 855 (3.23A)
b5 CN H -7.2 MET 793(3.22A) GLY 796 (3.35A) pi-H
LYS 745(3.29A)
b6 CH2=CH2 H -8.3 Non LEU 718 (4.24A) pi-H
b7 CH3 F -7.4 Non LEU 718 (4.16A) pi-H
b8 CH3 CH3 -6.9 Non LEU 718 (4.09 A) pi-H
LEU 718 (4.04 A) pi-H
b9 CH3 Cl -7.4 CSO 797(3.21A) Non
LYS 745 (2.90)
b10 CH3 OCH3 -7.7 LYS 745(3.32A) Non
GLY 724(3.51A)
b11 CH3 CN -8.2 ASP 855 (3.25A) LEU 718 (4.14A) pi-H
GLY 721(3.21A)
b12 CH3 CH2=CH2 -7.6 MET 793(3.16A) GLY 796 (3.54A) pi-H
b13 F F -7.1 MET 766(3.62A) LEU 718 (4.03A) pi-H
MET 793(3.36A) LEU 718 (3.87A) pi-H
b14 CH3 CH3 -7.8 MET 793(3.14A) GLY 796 (3.37 A) pi-H
b15 Cl Cl -7.2 GLY 721(3.01A) Non
b16 OCH3 OCH3 -8.3 MET 793(3.46A) LEU 718 (4.15A) pi-H
LEU 718 (4.02A) pi-H
b17 CN CN -7.1 Non LEU 718 (4.21A) pi-H
b18 CH2=CH2 CH2=CH2 -8.2 Non LEU 718 (4.23 A) pi-H
b19 Cl F -6.7 GLU 762(3.74A) GLY 796 (3.51 A) pi-H
MET 793(3.22A)
b20 Cl CH3 -7.9 GLU 762(3.05A) LEU 718 (4.19 A) pi-H
LYS 745(3.09A)
b21 Cl Cl -7.1 GLU 762(3.20A) LEU 718 (4.27 A) pi-H
LYS 745(3.09A)
b22 Cl OCH3 -7.5 LYS 745(3.47A) Non
b23 Cl CN -6.9 Non VAL 726 (4.50A) pi-H
b24 Cl CH2=CH2 -7.1
b25 OCH3 F -7.5 MET 793(3.21A) GLY 796 (3.32A) pi-H
b26 OCH3 CH3 -8.0 THR 854(3.01A) Non
ASP 855 (3.12A)
b27 OCH3 Cl -7.4 Non LEU 718 (4.23A) pi-H
b28 OCH3 OCH3 -6.9 Non LEU 718 (3.68A) pi-H
b29 OCH3 CN -7.7 LYS 745(3.23A) Non
b30 OCH3 CH2=CH2 -7.8 MET 793(3.22A) GLY 796 (3.52A) pi-H
b31 CN F -7.4 GLY 721(3.19A) Non
LYS 745(3.43A)
b32 CN CH3 -6.8 LYS 745(3.19A)
b33 CN Cl -7.1 LEU 718 (3.76A) pi-H
b34 CN OCH3 -8.3 ASP 855 (3.25A) LEU 718 (4.14A) pi-H
b35 CN CN -7.7 MET 793(3.22A) LEU 718 (4.08A) pi-H
LYS 745(3.49A) LEU 718 (4.00 A) pi-

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LYS 745 3.40A) GLY 796 (3.50A) pi-H

b36 CN CH2=CH2 -7.3 LYS 745(3.37A) VAL 726 (4.49A) pi-H
VAL 726 (3.95A) pi-H
b37 CH2=CH2 F -7.3 Non PHE 723 (4.26A) H-pi
GLY 719 (3.81A) pi-H
b38 CH2=CH2 CH3 -7.1 Non LEU 718 (3.94A) pi-H
VAL 726 (3.93 A) pi-H
b39 CH2=CH2 Cl -8.0 Non GLY 796 (3.32A) pi-H
b40 H OCH3 -8.4 MET 793(3.22A) GLY 796 (3.35A) pi-H
b41 CH2=CH2 CN -7.8 Non LEU 718 (4.32A) pi-H
LYS 745 (3.81A) pi-cation
b42 CH2=CH2 CH2=CH2 -7.7 Non LYS 745 (4.03A) pi-cation
Imatinib -8.3 Non LYS 745 (3.58A) pi-cation

b6 b11

b16 b18

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b26 b34

b39 b40

Imatinib
Scheme 2. 2D schematic diagram illustrating the target compound's docking model (for
the best compound) with the target 4WKQ protein.
The table consists of details concerning the energy Overall, the findings indicate that the analyzed
of binding (in kcal/mol), hydrogen bond ligands display varying degrees of binding affinity
interactions and non-hydrogen bond interactions to the target 4WKQ protein with some ligands
for each compound. Imatinib, a widely known exhibiting stronger interactions than others. The
tyrosine kinase inhibitor (TKI) targeting ABL1 was presence of hydrogen bonds and non-hydrogen
made use of as a reference in this analysis. bond interactions contributes to the stability of the

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Sarah Sattar Jabba, Mohammed Hassan Mohammed

ligand-protein complexes, this variability Compounds demonstrated comparable or stronger

influences their binding energies. The involvement binding energies than imatinib. For example,
of specific amino acid residues, such as MET 793, compound b40 exhibited the highest binding energy
LYS 745, LEU 718, and GLY 796, was noted in of -8.4 kcal/mol. Compounds b6 and b11, b16, b18,
significant interactions with the ligands. b26, b34, and b39 also showed comparable strong
Binding Energy: The binding energy represents the binding energies, interacting with key amino acid
strength of interaction between the TKI and the residues. Compound b10 displayed a binding
target 4WKQ protein. Higher negative values energy of -7.7 kcal/mol.
indicate stronger binding affinity. Imatinib Some compounds, such as b1, b3, b4, b5, and b25,
exhibited a binding energy of -8.3 kcal/mol, while exhibited slightly lower binding energies ranging
the analyzed compounds (a1-a42) ranged from -6.8 from -6.7 to -7.2 kcal/mol. However, they still
to -8.7 kcal/mol. interacted with key amino acid residues, albeit in
In comparison to Imatinib, several compounds, different ways, suggesting potential binding
including comp-a23, a34, and a35, displayed the affinity. Compound b23 showed a moderate energy
higher negative values of binding energies of -8.4, of binding (-6.9 kcal/mol)
-8.5, and -8.7 kcal/mol, respectively. This suggests Overall, these findings indicate that several
stronger binding affinities and potentially more compounds, including, b6, b11, b16, b18, b34,
significant interactions. compounds a6 and a8 b39and b40, exhibit comparable or stronger binding
showed similar binding energies and interacted energies and interact with key amino acid residues,
with key amino acid residues. Other compounds, suggesting their potential as lead candidates in
a7, a20, a21, and a32 exhibited slightly lower comparison to imatinib.
binding energies but still interacted with key amino
acid residues, albeit in distinct ways. 4. Conclusions
Hydrogen bond and non-hydrogen bond Via our computational docking examination, we
interactions, such as pi-H and pi-cation interactions, have obtained beneficial understandings right into
also contribute to ligand binding and stabilization. the binding interactions and strength between a
Imatinib showed a pi-cation interaction with LYS newly developed tyrosine kinase inhibitor (TKI)
745 (3.58 Å), while the analyzed compounds and its target, the 4WQK tyrosine kinase. This
displayed a variety of hydrogen bond and non- highlights the possibility of structure-based drug
hydrogen bond interactions involving different design methods in speeding up the exploration and
residues, including MET 793, LYS 745, LEU 718, improvement of targeted therapies. Our results
GLY 796, THR 854, ASP 855, GLU 762, PHE 856, provide guidance for further experiments, such as
and LEU 788. Some compounds exhibited the production and assessment of the intended TKI
interactions like Imatinib, while others as a possible anticancer drug. More precisely, we
demonstrated distinct hydrogen bonding and non- evaluated the TKI's efficiency, affinity for binding,
hydrogen bond patterns. and level of competition in blocking ABL1, with
In conclusion, based on the provided data, the intention of evaluating its potential as a targeted
compounds such as a6, a8, a23, a34, and a35, treatment for malignancies driven by ABL1. This
exhibit promising binding affinities and show research can help develop and optimize the TKI
distinct interactions compared to Imatinib. further, which could result in the development of a
Therefore, these compounds have the potential to more effective treatment option for patients with
be considered as lead or promising candidates for cancers linked to ABL1.
further evaluation as TKIs.
In comparison to imatinib, which exhibited a Acknowledgment
binding energy of -8.3 kcal/mol and formed a pi- We extend our heartfelt gratitude to the individuals
cation interaction with LYS 745 at 3.58Å, the associated with the Department of Pharmaceutical
newly designed TKI shows energy of binding Chemistry, Faculty of Pharmacy, University of
ranging from -6.7 to -8.4 kcal/mol, which suggests Baghdad, for their invaluable support and
varying degrees of interaction strength with the assistance during the progression of this research
target protein and interaction profiles. endeavor.

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Sarah Sattar Jabba, Mohammed Hassan Mohammed

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