INTRODUCTION:
Cancer is an elusive disease to cure
causing the mortality rate of patients with cancer to remain high despite
today’s new technologies and treatments1-3. Around 9.6 million
people died in 2018 because of cancer and the number of cancer patients is increasing every
year. Due to the ineffectiveness of available conventional
chemotherapy, novel anticancer compounds are still needed4,5. Currently, computer-aided drug
discovery (CADD) methods are done as a strategy for discovering a novel
anticancer compound6-8.
The CADD methods with various powerful tools are
making the discovery of a novel drug compound more convenient, thus the identification
process of drug target, design, and optimization of molecule design have become
easier using CADD methods9-13. One target of a novel anticancer
compound is mutant p53. Mutant p53 was selected as a novel anticancer compound
target because it accumulates in large numbers in the cell nucleus14.
The existence of mutant p53 provides new transcription activities which are
dubbed gain of function (GOF), negative dominant effects, and loss of tumor
suppressor genes activities15-17, which account for increasing
malignancies, increasing cell cancer proliferation18,19, and
increasing resistance to conventional chemotherapy20. Mutant p53 has an important amino acid
residue, Cys-124, which is located in the pocket between the L1 loop and the S3
sheet (L1/S3). This pocket is found in various p53, not located in the p53
mutation “hot spot” and has solvent-accessible
surface area (SASA) values between 6-11 Å which is much bigger than wild type
p53 value 0.43 Å21. Cys-124 in this pocket becomes an
interesting target for a novel anticancer compound22.
Cys-124 has a nucleophilic property, and as a novel
anticancer agent the small molecule can fulfill the criteria to be alkylated by
–SH group Cys-124 via the Michael addition reaction23,24. The
Michael addition product leads to a change of mutant p53 conformation into
something similar to the wild type p53 conformation25. This change will reactivate the ability of mutant
p53 to induce apoptosis through the p53 network system26-29. The small anticancer
molecule with the mechanism as reactivator of mutant p53 to induce apoptosis was dubbed as a
mutant p53 reactivator. The success
of using a small mutant p53 reactivator molecule can potentially cure 50% of
cancer cases30. Employing a small p53 reactivator molecule
selectively targeted to mutant p53 can reduce the toxic effect on the normal
cells31-33. The ability of a small p53 reactivator molecule to
change the conformation of mutant p53 that has accumulated in large numbers in
cancer cell nuclei results in apoptosis which is much more powerful than wild
type p53 in the normal cell14.
3-carbethoxy-4-phenyl-but-3-en-2-one is a small
molecule designed as a mutant p53 reactivator using a fragment-based drug
design method. This molecule
has an important α, β-unsaturated carbonyl scaffold in order
to be alkylated by –SH group of Cys-124 of mutant p53. The alkylation process
results in a Michael addition product. The corresponding Michael addition
product leads to a change of mutant p53 conformation into one similar to wild
type p53 conformation which can subsequently bind to DNA in order to
reactivate the p53 network system to initiate apoptosis. The proposed mechanism
of 3-carbethoxy-4-phenyl-but-3-en-2-one as a mutant p53 reactivator is
displayed in Figure 1.
This research aimed to compare a novel compound 3-carbethoxy-4-phenyl-but-3-en-2-one
and methylene quinuclidinone (MQ)
compound (Figure 2) to determine its potential as a ligand to reactivate the
ability of mutant p53 to induce apoptosis using molecular docking. The AutoDock
Vina was employed as molecular docking software34 with three mutant
p53 crystal structures (PDB code: 2BIM, 2J1Y, and 2J21) as the protein target. MQ was used as a standard in this research, which
is a metabolism product of PRIMA-1. It is a well-known compound as a mutant p53
reactivator35,36. The results obtained from the
molecular docking study were scoring of the function of binding energy and
ligand-receptor interactions34.The molecular docking study
demonstrated 3-carbethoxy-4-phenyl-but-3-en-2-one had better binding energy value
than MQ, especially in crystal structures 2BIM and 2J21. Visual inspection of
the docking results determined docking of 3-carbethoxy-4-phenyl-but-3-en-2-one
in the binding pocket of three mutant p53 crystal structures, forming hydrogen
bond or hydrophobic interaction with important amino acid residue Cys-124. The
distance between the double bond of α, β-unsaturated ketone in
3-carbethoxy-4-phenyl-but-3-en-2-one with –SH group Cys-124 was shorter than
MQ. Based on these results, it was concluded 3-carbethoxy-4-phenyl-but-3-en-2-one
has better activity than MQ as a potential mutant p53 ligand to reactivate the
ability of mutant p53 to induce apoptosis.
Figure 1. Proposed mechanism of 3-carbethoxy-4-phenyl-but-3-en-2-one
as a mutant p53 reactivator (adopted from14,15)
|
|
|
|
3-carbethoxy-4-phenyl-but-3-en-2-one
|
MQ
|
Figure 2. Structure of 3-carbethoxy-4-phenyl-but-3-en-2-one
and methylene quinuclidinone
(MQ).
MATERIAL AND METHODS:
The mutant p53 crystal structures were acquired from
protein data bank with PDB ID of 2BIM37, 2J1Y38 and 2J2138
as the reference structure. The structure of 3-carbethoxy-4-phenyl-but-3-en-2-one
was selected as the ligand. All computational and calculation simulations were
done on a Windows 10 machine with Intel® Core i7-8550U (@ 4.0GHz) as the
processors and 8.00GB of RAM. AutoDock Vina34, MarvinSketch 18.2539,
Discovery Studio 2017 R2 Client40, and LigPlot+ v.2.141
applications were employed in this research.
Structure crystal preparation as a virtual molecular
target:
The crystal structures of mutants p53 with the PDB id
2BIM, 2J1Y, and 2J21 were downloaded from the PDB website (http://www.rscb.org).
Every crystal structure of mutants p53 (2BIM, 2J1Y, and 2J21) was prepared by
Discovery Studio software to eliminate water molecules, crystal structure
subunit A, C, and D (we only used subunit B), and Zn2+ ion
discovered in the every pdb file of mutants p53 (2BIM, 2J1Y, and 2J21).
After saving the files in corresponding pdb files of 2BIM, 2J1Y, and
2J21, these files were ready to be used to conduct simulations employing
AutoDock Vina as docking software.
Ligand preparation:
The 3-carbethoxy-4-phenyl-but-3-en-2-one and MQ
ligands were drawn and underwent a conformational search to find the most stable
conformer from 10 seeds by Marvin Sketch 18.25. The most stable conformers of 3-carbethoxy-4-phenyl-but-3-en-2-one
and MQ were saved in corresponding pdb files (ligand.pdb) and
used for the docking simulations.
Molecular docking simulation:
Molecular docking simulation for 3-carbethoxy-4-phenyl-but-3-en-2-one
and MQ ligands used Auto Dock Vina. Subsequent molecular dockings were set as
follows. The binding pocket in the docking configuration file was defined as
Cys-124 as a center of grid box 40
4040. The exhaustiveness value used was 8.
The grid spacing was set to 1A. The ligand was docked independently ten times
in the binding pocket of every type of mutant p53 (2BIM, 2J1Y, and 2J21). The
best pose of each ligand-crystal structure of mutant p53 was selected as the
pose with the lowest binding energy.
Visualization and interaction of docking result:
Visualization of docking result was performed using
Discovery Studio 2017 R2 Client softwares. Ligand-mutant p53 interaction
diagram was prepared using LigPlot+ software.
RESULTS AND DISCUSSION:
This research was part of the process to find a new
anticancer drug with a mechanism as a mutant p53 reactivator. One of the novel
candidate molecules with such mechanism was 3-carbethoxy-4-phenyl-but-3-en-2-one.
This molecule was the result of employing a fragment-based drug design method. 3-carbethoxy-4-phenyl-but-3-en-2-one
was a small molecule with α, β-unsaturated carbonyl scaffold.
The existence of α, β-unsaturated carbonyl was important
because it is responsible for its activity as a mutant p53 reactivator. α,
β-unsaturated carbonyl scaffold was added by the phenyl and esther
groups in order to increase its ability as a mutant p53 reactivator. The
additional groups allowed some additional interactions of 3-carbethoxy-4-phenyl-but-3-en-2-one
with amino acid residues near its binding pocket. In this part, the potential
activity from a novel compound 3-carbethoxy-4-phenyl-but-3-en-2-one as the
ligand was investigated to reactivate the ability of mutant p53 to induce
apoptosis.
The potential of 3-carbethoxy-4-phenyl-but-3-en-2-one
as a reactivator mutant p53 was concluded from the binding energy scoring
function (Kcal/mol) and distance between the double bond of α, β-unsaturated
ketone of 3-carbethoxy-4-phenyl-but-3-en-2-one with –SH group of Cys-124 of
mutant p53. These values were produced from molecular docking of 3-carbethoxy-4-phenyl-but-3-en-2-one
with mutant p53 crystal structures 2BIM37, 2J1Y38, and
2J2138 as target proteins.
The Auto Dock Vina was employed as a molecular docking
software. The advantages of using AutoDock Vina were a high-speed and
high-accuracy process in providing bound conformation of a small molecule
(ligand) to the macromolecular target (protein) and providing prediction with
its binding energy34. Three types of mutant p53 crystal structures
were used because they differ from one another in the type and position of
amino acids that undergo mutations. The three types of mutations are part of
the "hot spot" missense mutation p53 and represented the most common
types of cancers42. The 2BIM, 2JIY, and 2J21 are the p53 mutant
crystal structures with a mutation in Arg-273-His37, Gly-245-Ser38,
and Arg-245-Trp38, respectively. Three types of crystal structures
were employed to determine the potential of 3-carbethoxy-4-phenyl-but-3-en-2-one
as the ligand to reactivated mutant p53 in many types of cancer with many types
of p53 mutation.
Binding energy scoring function (Kcal/mol) of the
molecular docking study of the ligand 3-carbethoxy-4-phenyl-but-3-en-2-one and
MQ in mutant p53 crystal structures, i.e. 2BIM, 2J1Y, and 2J21 are
presented in Table I. This study shown the lowest binding energy value of bound
conformation for every ligand in every mutant p53 crystal structure. The 3-carbethoxy-4-phenyl-but-3-en-2-one
had a lower binding energy scoring function than MQ in 2BIM and 2J21. 2BIM’s
and 2J21’s amino acid residues formed more interactions with 3-carbethoxy-4-phenyl-but-3-en-2-one
than MQ (Figures 3a-c). MQ had a lower binding energy scoring function than 3-carbethoxy-4-phenyl-but-3-en-2-one
in 2J1Y. The main contribution of hydrogen bonding of Cys-124 2J1Y with MQ
might decrease its binding energy scoring function greater than hydrophobic interaction
of Cys-124 2J1Y with 3-carbethoxy-4-phenyl-but-3-en-2-one, although 2J1Y’s
amino acid residues formed more interactions with 3-carbethoxy-4-phenyl-but-3-en-2-one
than MQ (Figures 4a-c).
Table 1. Scoring function of binding energy (Kcal/mol)
ligand in various crystal structures.
|
Ligands
|
Crystal
structures
|
|
2BIM
|
2J1Y
|
2J21
|
|
3-carbethoxy-4-phenyl-but-3-en-2-one
|
-4.00
|
-0.50
|
-4.60
|
|
MQ
|
-3.60
|
-2.80
|
-3.70
|
Visual inspection of docking pose of 3-carbethoxy-4-phenyl-but-3-en-2-one
in mutant p53 revealed 3-carbethoxy-4-phenyl-but-3-en-2-one docked in the
mutant p53 binding pocket which is shown in Figures 3a-c. Analysis of 3-carbethoxy-4-phenyl-but-3-en-2-one
-mutant p53 interactions revealed several interactions between 3-carbethoxy-4-phenyl-but-3-en-2-one
with some amino acid residues of mutant p53 were found as displayed in Figure
3. 3-carbethoxy-4-phenyl-but-3-en-2-one formed interactions with important
amino acid residue, Cys-124, through hydrophobic interactions in mutant p53
crystal structure 2BIM and 2J1Y or hydrogen bonding in mutant p53 crystal
structure 2J21 (Figures 3a-c). Interaction between 3-carbethoxy-4-phenyl-but-3-en-2-one
with Cys-124 corresponded with the interaction between MQ with Cys-124 and
therefore demonstrated the potential of 3-carbethoxy-4-phenyl-but-3-en-2-one as
a mutant p53 reactivator.
Some other amino acid residues in crystal structure
mutant p53 (2BIM, 2J1Y, and 2J21) were involved in the interaction with 3-carbethoxy-4-phenyl-but-3-en-2-one
through either hydrophobic interaction or hydrogen bonding (Figures 3a-c). They
were involved in the interaction with 3-carbethoxy-4-phenyl-but-3-en-2-one
because of their distance which
was less than 4 Å.
Leu-114 and Pro-142 were two types of amino acid residues in 2BIM, 2J1Y, and
2J21 which were always involved in hydrophobic interaction. Thr-123 was the
only amino acid residue in 2J1Y which was involved in hydrogen bonding with 3-carbethoxy-4-phenyl-but-3-en-2-one.
All types of involving interactions affected the interaction strength of 3-carbethoxy-4-phenyl-but-3-en-2-one
with the mutant p53. The strength of interaction was reflected in the binding
energy scoring function.
The docking results of the 3-carbethoxy-4-phenyl-but-3-en-2-one
and MQ in mutant p53 (2BIM, 2J1Y, and 2J21) crystal structure informed that the
distance between the double bond of α, β-unsaturated ketone of
both ligands with –SH group Cys-124 in each crystal structure. The Cys-124
amino acid residue was pivotal as it was targeted by mutant p53 reactivator
compounds through alkylating the double bonds α,β-unsaturated
ketone by the -SH group Cys-124 via the Michael addition mechanism35,44.
Therefore, the distance between the double bonds of α, β-unsaturated
of 3-carbethoxy-4-phenyl-but-3-en-2-one and MQ to the -SH group Cys124 gave a
prediction about the possibility that the alkylation process would determine
the activity as the mutant p53 reactivator compound. The 3-carbethoxy-4-phenyl-but-3-en-2-one
which was docked in the 2BIM, 2J1Y, and 2J21 binding pocket had a shorter
distance of double bonds of α, β-unsaturated than the MQ as
shown in Table 2 indicating that it was easier to be alkylated by the -SH group
Cys-124 and consequently would increase its reactivation activity. Based on
this computational study, 3-carbethoxy-4-phenyl-but-3-en-2-one was predicted to
have a better reactivation activity than MQ to mutant p53 especially in
mutation type Arg-273-His and Arg-245-Trp.
Table 2. The distance between the double bonds of
α, β-unsaturated ketone and the –SH group Cys-124 mutant p53 (Å)
|
Ligands
|
Crystal
structures
|
|
2BIM
|
2J1Y
|
2J21
|
|
3-carbethoxy-4-phenyl-but-3-en-2-one
|
6.44
|
7.08
|
5.97
|
|
MQ
|
7.89
|
7.79
|
6.86
|
CONCLUSION:
The effort to discover anticancer drugs is a
time-consuming and costly process. Employing molecular docking study to 3-carbethoxy-4-phenyl-but-3-en-2-one
was intended to identify its ability as a ligand to reactivate mutant p53
quickly. In this work, three types of mutant p53 2BIM, 2J1Y, and 2J21 crystal
structures were used as protein targets in molecular docking simulations of 3-carbethoxy-4-phenyl-but-3-en-2-one.
The use of three types of crystal structures was done in order to predict its
potential as the ligand to reactivate mutant p53 with a different type of
mutation. The MQ was used as the standard since it has been known for having anticancer
activity and its ability to reactivate mutant p53 as compared to 3-carbethoxy-4-phenyl-but-3-en-2-one ligand. The result of molecular
docking demonstrated that 3-carbethoxy-4-phenyl-but-3-en-2-one had
lower binding energy scoring function than MQ in 2BIM and 2J21 but had higher
binding energy scoring function than MQ in 2J1Y. Visual inspection identified 3-carbethoxy-4-phenyl-but-3-en-2-one
and MQ docked in the binding pocket of mutant p53 2BIM, 2J1Y, and 2J21 crystal
structure. The distance between double bonds of α, β-unsaturated
of 3-carbethoxy-4-phenyl-but-3-en-2-one to the -SH group of Cys124 was shorter
than MQ. Based on the molecular docking study results, the 3-carbethoxy-4-phenyl-but-3-en-2-one
compound was found to be a potential ligand for mutant p53 and predicted to
give a better activity especially in cancers with mutation type Arg-273-His and
Arg-245-Trp than MQ as a mutant p53 reactivator.
ACKNOWLEDGEMENT:
This research was supported by the Rekognisi Tugas
Akhir (RTA) project of Universitas Gadjah Mada.
CONFLICT OF INTEREST:
The authors declare no conflict of
interest.
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