International Journal of Application or Innovation in Engineering & Management (IJAIEM)
Web Site: www.ijaiem.org Email: editor@ijaiem.org, editorijaiem@gmail.com
ISSN 2319 - 4847
Special Issue for National Conference On Recent Advances in Technology and Management
for Integrated Growth 2013 (RATMIG 2013)
Inhibition Studies of Antileukemic PTK Type
Protein 1(ABL1) by Small Molecule, chromen-4one based Mimetic
*Dr. Nitu Gupta1, Dr. Bapu Shende2 Dr. Indrajeet Jamane3 and Miss Meghna Suryawanshi4
1
Dr. Nitu Gupta, Asst. Professor, Dept. of Chemistry, Guru Nanak Institute of Engineering and Management, Nagpur(MS)
neetusgupta@rediffmail.com
2
Dr. Bapu Shende, Asst. Professor, Dr. Ambedkar college, Nagpur(MS)
bapushende@gmail.com
2
Dr. Indrajeet Jamane, Sr. Manager research & Development, Cheminova India Ltd, Ahemedabad (GJ)
4
Miss Meghna Suryavanshi, Guru Nanak Institute of Engineering and Technology, Nagpur(MS)
Suryawanshi.meghna@gmail.com
Inhibition Studies ofABSTRACT
Antileukemic PTK Type
Title of your paper for IJAIEM
Informatics and computational design methods were used to create new molecules that could potentially bind
to
antileukemic(PTK) type proteins which play an important
role in regulating
cell growth and cell3 division and are often involved in
1
2
First
Author
, Second
Author homolog
and Third
author
tumor formation.4 The v-abl Abelson
murine
leukemia
viral oncogene
1(ABL1)
having PDB code 2F4J which is a type
of Protein Tyrosine Kinase(PTK) Protein (oncogene)
appears
to
be
responsible
for
the
blast
crisis stage of Chronic Myelogenous
1
FirstofAuthor
Affiliation with address
Leukemia(CML) as well as the initial chronic phase
the diseases.
john.doe@email.com
Designed molecule that mimic the roles of PTK
2 inhibitor can occupies the kinase pocket of target protein, blocking the access to
Author
Affiliation
with address
ATP, and thus prevents the phosphorelation of Second
downstream
effect
of molecules.
Hence the development of PTK inhibitors blocking
john.doe@email.com
signaling pathways is considering a promising and innovative
approach for drug development in the treatment of patients with
CML.8
3
Third Author Affiliation with address
john.doe@email.com
The goal of our study was to create new putative mimetics
that could bind to targeted antileukemic protein. Five new small
molecule were designed that formed stable complexes with 1(ABL1) having PDB code 2F4J protein. Drug likeness studies
performed on the designed molecules, as well as previous experimental and pre-clinical studies on nearby same agents, strongly
suggest that the designed molecules may indeed be promising drug candidates. Computer based molecular design promises to
accelerate drug research by predicting potential effectiveness of designed molecules prior to laborious experiments and costly preclinical trials.
Keywords: Leukemia cancer, anticancer drug research, small molecule mimetic, PTK, CML.
Introduction
Leukemia is a cancer of blood cells, rated on top most type of cancer followed by brain tumors in childrens 1,2. Leukemia
stands as a major childhood killer cancer disease ie has a major proportion among the childrens, in boys 35% and in girls
it is of 33% below the age of fourteen.3
The recent study reveals that ,the v-abl Abelson murine leukemia viral oncogene homolog 1(ABL1) having PDB code
2F4J which is a type of Protein Tyrosine Kinase(PTK) Protein (oncogene) appears to be responsible for the blast crisis
stage of Chronic Myelogenous Leukemia(CML) as well as the initial chronic phase of the diseases. So PTK inhibitors
promises to be an important advance in the treatment of patients with CML. PTK play an important role in regulating
cell growth and cell division and are often involved in tumor formation4 .
Organized By: GNI Nagpur, India
International Journal of Application or Innovation in Engineering & Management (IJAIEM)
Web Site: www.ijaiem.org Email: editor@ijaiem.org, editorijaiem@gmail.com
ISSN 2319 - 4847
Special Issue for National Conference On Recent Advances in Technology and Management
for Integrated Growth 2013 (RATMIG 2013)
In present study Inhibition studies were carried out between Protein Tyrosine Kinase (PTK) type, v-abl Abelson murine
leukemia viral oncogene homolog 1(ABL1) having PDB code 2F4J, which play an important role in regulating cell
growth and cell division1,2 as a receptor and a series of derivatives of Chromen-4-one based compounds as a substrate
(ligand) 3.
The number of mimetic(derivatives) of chromen-4-one based compounds or molecules were designed using molecular
mechanics techniques by substituting different groups or atoms at R1 R2 and R3 positions. The designed molecules were
interacted with selected enzyme using computer simulation techniques. The binding free energy (ΔG) per mole were
calculated, which is the sum of intermolecular interactions between ligand and protein, (van der Waals + H-bond +
electrostatic) and the internal static energy of the ligand and which can be represented by the equation,
∆Gbind=∆Gvdw+∆Ghydrophobic+∆GH-bond+∆GH-bond(chg)+∆Gdeformation+ ∆G0
Among the studied molecules, a few number of mimetic shows negative free energy and hence can be studied as potent
PTK inhibitor or a potent v-abl Abelson murine leukemia viral oncogene homolog 1(ABL1) inhibitors.
Methodology
The v-abl Abelson murine leukemia viral oncogene homolog 1(ABL1) having PDB code 2F4J which is a type of Protein
Tyrosine Kinase(PTK) Protein (oncogene) was selected as the target enzyme. Its 3D electronic structure having natural
inhibitor (Aurora kinase inhibitor VX680 109,110 ,CYCLOPROPANE CARBOXYLIC ACID {4-[4-(4-METHYLPIPERAZIN-1-YL)-6-(5-METHYL-2H PYRAZOL-3-YLAMINO)-PYRIMIDIN-2-YLSULFANYL}-AMIDE) was
procured from protein repository15,16 databank. The position of natural inhibitor was selected as the centre of active site
and it was removed before docking the ligand.
The series of compounds/mimetic/a small molecules which are the derivatives of 2-(3-Hydroxy-1-methyl-piperidin-4yl)-chromen-4-one, were designed using computer based designing tools ChemOffice17 and their 3D geometries were
finalized by minimizing the total energy content using molecular mechanics techniques. While finalizing the geometry of
small molecules, global minima were achieved and confirmed.
2-(3-Hydroxy-1-methyl-piperidin-4-yl)-chromen-4-one which is selected as a lead compound provides three
substitution sites as shown in figure 1.
R1
O
OH
R2
O
R3
N
Me
2-(3-Hydroxy-1-methyl-piperidin-4-yl)-5,7,8-trimethyl-chromen-4-one
Figure. 1
Figure 2: 3-D Conformation of Ligand 2-(3-Hydroxy-1-methylpiperdin-4-yl)-5,7,8-trimethyl-chromen-4-one
Series of small mimetic/molecules were designed from lead compound by substituting at position R1 R2 and R3 by the
pharmacophores -H, -CH3, -Cl, -Br, -F, -C2H5, -C3H7, -CH2OH, -NH2, -NHCH3, -CH2CH2NHCH3, -NHC6H5, CONH2, -NO2, -C6H4Cl, -C6H4OH, -C6H4F, -C6H4CCl3, -C6H4Br, -C6H3Cl(OH), -C6H3(OH)2, -C6H5,
C5H3NMe(OH), -CONH2, -C6H4NH2, -C6H4NO2, -C6H4OCH3, n-C6H11,
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International Journal of Application or Innovation in Engineering & Management (IJAIEM)
Web Site: www.ijaiem.org Email: editor@ijaiem.org, editorijaiem@gmail.com
ISSN 2319 - 4847
Special Issue for National Conference On Recent Advances in Technology and Management
for Integrated Growth 2013 (RATMIG 2013)
-CH2C6H4Cl, n-C3H7, i-C3H7, -n-C4H9, n-C6H13, -C6H5CH2, c-C6H11, -C5H5CH2,
t-C4H9, n-C4H9.
The list of designed molecules along with substituted pharmacophores is prepared only for those which are successfully
achieved global minima. The database of these molecules prepared and stored as an electronic library for docking
process.
To ascertain the validity of the 3D designe, various thermodynamic properties were calculated in-silico using chemdraw.
These molecules then subjected to docking studies with the binding site of 2F4J enzymes using computer based tools
Argus18 and Autodock13,14.
Results
The selected mode of docking was performed using Genetical Algorithms which provides most intelligent docking
positions. The process gives the binding energy as the measure of strength of interactions between small molecule and
enzyme. Table 2 shows the results of binding energy of various docked molecules.
From the series of molecules docked by using different pharmacophore mentioned above and those who attained global
minima, the docking results of only best five molecules are shown in CPK and wireframe modes in figure 3,4,5,6 and 7.
As well Table 3 shows the number and distance of hydrogen bondings involved in the complex formation between
enzyme and mimitic. It also shows the Amino acid involved in hydrogen Bonding, Atom no. having hydrogen bonding
with A.A., Group interacting of Protein and Group interacting of Ligand.
Table 1: The best five docked complex(Mol.), selected from Substituted Chromene-4-one based lead compound
showing the binding energy along with the possible hydrogen bonding with amino acids of protein 2F4J
Mol.
Molecular
Docking
Total
Amino acid involved in
Hydrogen bonding
No.
formula
energy ∆G
hydrogen
hydrogen bonding
distance in A.
in kcal/mol
bonding
23
C21H18Cl3NO3
-13.61
21
C21H19Cl2NO4
1
C21H20ClNO3
-13.4844
2
3
C11H20ClNO4
-13.1298
3
14
C21H20BrNO5
-12.8343
4
-13.5101
2
4
131 GLN
132 ASN
83 LEU
83 LEU
131 GLN
12 GLU
145 ASP
145 ASP
131 GLN
83 LEU
83 LEU
81 GLU
83 LEU
83 LEU
131 GLN
2.8441
2.5226
2.3150
2.5520
2.6347
2.9485
2.6403
2.2966
2.8749
2.8787
2.1661
2.1010
2.2222
2.0597
2.7317
Graphical representation of Substituted Chromene-4-one based molecule (mimic) interacting with 2F4J.
Organized By: GNI Nagpur, India
International Journal of Application or Innovation in Engineering & Management (IJAIEM)
Web Site: www.ijaiem.org Email: editor@ijaiem.org, editorijaiem@gmail.com
ISSN 2319 - 4847
Special Issue for National Conference On Recent Advances in Technology and Management
for Integrated Growth 2013 (RATMIG 2013)
Fig.3- Molecule 23- Dichloro-8-(2-chloro-phenyl)-2-(3-hydroxy-piperidin-4-yl)-chromene-4-one interacting with 2F4J.
Interaction with131 GLN , 132 ASN
Fig.4- Molecule 21-7-chloro-8-(2-chloro-phenyl)-5-hydroxy-2-(3-hydroxy-1-methyl-piperidin-4-yl)-chromene4-one interacting with 2F4J. Interaction with 83 LEU, 83 LEU, 131 GLN, 12 GLU
Fig.5- Molecule no.1 8-(2-chloro-phenyl)-2-(3-hydroxy-1-methyl-piperidin-4-yl)-chromene-4-one sma interacting with
2F4J. Interaction with 145 ASP, 145 ASP
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International Journal of Application or Innovation in Engineering & Management (IJAIEM)
Web Site: www.ijaiem.org Email: editor@ijaiem.org, editorijaiem@gmail.com
ISSN 2319 - 4847
Special Issue for National Conference On Recent Advances in Technology and Management
for Integrated Growth 2013 (RATMIG 2013)
Fig.6- Molecule 41- 8-(2-chloro-phenyl)-5-hydroxy-2-(3-hydroxy-1-methyl-piperidin-4-yl)-chromene-4-one molecule
no. 3 interacting with 2F4J Interaction with 131 GLN, 83 LEU, 83 LEU
Fig.7- Molecule 14- 5-8-(2-bromo-phenyl)-5,7-dihydroxy-2-(3-hydroxy-1-methyl-piperidin-4-yl)-chromene-4-one small
molecule no.14. interacting with 2F4J. Interaction with 81 GLU, 83 LEU, 83 LEU, 131 GLN
Molecule No. with (2F4J) &
Interaction with Amino Acid
Hydrogen
bond
distance
Amino acid
involved in
hydrogen
bonding
Atom no. having
hydrogen bonding
with A.A.
2.8441
2.5226
131 GLN
132 ASN
983(O)
995(O)
2.3150
2.5520
2.6347
2.9485
83 LEU
83 LEU
131 GLN
12 GLU
595(O)
592(N)
983(O)
92(N)
-CO*OH
-N*H2
-CO*OH
-N*H2
2.6403
145 ASP
1084(N)
-N*H2
2.2966
145 ASP
1084(N)
-N*H2
Molecule No.
3 (2F4J)
2.8749
2.8787
2.1661
131 GLN
83 LEU
83 LEU
983(O)
595(O)
592(N)
-CO*OH
-CO*OH
-N*H2
Molecule No.
14 (2F4J)
2.1010
2.2222
2.0597
2.7317
81 GLU
83 LEU
83 LEU
131 GLN
575(O)
592(N)
595(O)
983(O)
-CH-CO*OH
-N*H2
-CO*OH
-CO*OH
Molecule No.
23 (2F4J)
Molecule No.
21(2F4J)
Molecule No.
1(2F4J)
* on an atom represents hydrogen bonding
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Group
interacting of
protein
-CO*OH
-CO*NH2
Group
interacting
of ligand
-O*H
(O17)
-O*H
(O17)
-O*H (R1)
-O*H (R1)
-O*H (17)
-N*(Me)
-O*- (O6)
-O*H
(O17)
-O*H
(O17)
-O*H (R1)
-O*H (R1)
-O*H (R2)
-O*H (R1)
-O*H (R1)
-O*H
(O17)
International Journal of Application or Innovation in Engineering & Management (IJAIEM)
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ISSN 2319 - 4847
Special Issue for National Conference On Recent Advances in Technology and Management
for Integrated Growth 2013 (RATMIG 2013)
In case of chromene-4-one based mimetic, most of the molecules show better hydrophobic, electrostatic and steric
interactions with the binding site of selected enzyme 2F4J. It is also reported that the maximum molecules having
hydrogen bonding with amino acid 145 Aspartic acid, 131 Glutamine, 81 Glutamic acid, 12 Glutamic acid, 132
Asparagine and 83 Leucine and hence helps in higher and stable interactions with enzyme.
These five molecules showing better interactions due to presence of charged groups and electron donating group at R1
and R2. It is also reported that –OH at R1 helps in increasing the interactions with enzyme. –OH at carbon atom 16 (C16
in figure 3.32) also helps in increasing interaction through hydrogen bonding.
It is also reported that the lead compound substituted chromene-4-one based is not toxic in nature and hence the
possibilities of not having toxic nature in their derivatives also. Though it is must for checking toxicity before going
ahead for research in vitro and in vivo.
It is reported that the maximum molecules having hydrogen bonding with amino acid 131 GLN, 132 ASN, 83 LEU, 12
GLU, 145 ASP, 81 GLU, and hence helps in higher and stable interactions with enzyme. It is also reported that all these
molecules are showing lower log P values (less than 5) which support the druglike properties.
Conclusion
The comprehensive study of docking interaction and binding energies of the enzyme 2F4J unveils that the newly
designed mimitic were in good conformity with the concept of drug design. These molecules gave favourable binding
interactions and GA docking energy values which are superior as compaired to the reference inhibitor.
Thus this study reports that all these Chromene-4-one based molecules especially molecule no. 23,21, 01, 03 and 14 can
inhibit the activity of PTK type, v-abl Abelson murine leukemia viral oncogene homolog 1(ABL1), which play a key
role in regulating cell growth and cell division and are oftenly involved in tumor formation by blocking signaling
pathways, provides an attractive target for designing novel antileukemia drug.
Hence the development of chromene 4-one based molecules can be a potent molecule for potent PTK inhibitors in
Leukemia cancer therapeutics resulting in the reduction and proliferation of the leukemic cells.
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International Journal of Application or Innovation in Engineering & Management (IJAIEM)
Web Site: www.ijaiem.org Email: editor@ijaiem.org, editorijaiem@gmail.com
ISSN 2319 - 4847
Special Issue for National Conference On Recent Advances in Technology and Management
for Integrated Growth 2013 (RATMIG 2013)
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AUTHOR
Dr. Nitu Gupta received the M.Sc. degree in organic Chemistry and Ph.D. in Medicinal Chemistry
from Rashtrasant Tukdoji Maharaj Nagpur University , Nagpur. She is now with GNIEM, Nagpur.
Organized By: GNI Nagpur, India