computational analyses of human kinome against egfr-tkis using homology modeling and molecular...
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Computational Analyses of Human Kinome against EGFR-TKIs using Homology Modeling
and Molecular Docking Approaches
Orathai SawatdichaikulInstitute of Food Research and Product Development
Adisak Ongsawas, Kiattawee Choowongkomon
Department of Biochemistry, Faculty of Science
Human Kinome
2G.Manning Science 2002
Human Kinome
3G.Manning Science 2002
Protein Tyrosine Kinases
4
31 sub-families
91 tyrosine kinase proteins
G.Manning Science 2002
5
OHHO
O
N
N
H2N
N N
P
O
O
OHOH
O
P
O
OH
O
P
O
OH
Adenosine-5'-triphosphate
OHHO
O
N
N
H2N
N N
P
O
O
OHOH
O
P
O
OH
Adenosine-5'-diphosphate
H2C
O
P
O
OH
HO
phosphotyrosine
Protein Tyrosine Kinases
6 Hanahan and Weinberg, Cell 2000
Protein Tyrosine Kinases
7
91 Human tyrosine kinase proteins
PDB(availabl
e)
Retrieve 3D-structure (PDB file)
Retrieve primary
sequence(s)
Sequence alignment
Homology modeling
Protein preparation
Molecular Docking
NoYes
8
The Structures of PTKs in Protein Data Bank (PDB)
Only 51 PTKs exist, other 40 PTKs still unavailable
9
91 Human tyrosine kinase proteins
PDB(availabl
e)
Retrieve 3D-structure (PDB file)
Protein preparation
Molecular Docking
NoYes Retrieve primary
sequence(s)
Sequence alignment
Homology modeling
10
11
91 Human tyrosine kinase proteins
PDB(availabl
e)
Retrieve 3D-structure (PDB file)
Protein preparation
Molecular Docking
NoYes Retrieve primary
sequence(s)
Sequence alignment
Homology modeling
ErbBs-TK inhibitors
EGFRs-TK inhibitors
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N
N
HN
NH
N
N
Lapatinib
0UN
Hydrazone
Gefitinib
Oxime inhibitor
AEE 788
Erlotinib
Neratinib
N
N
NH
O
O
O
O
O
NH
N
NO
N
NH
O
N
Cl
N
N
NH
ON
O
O
F
Cl
N
N
NH
NH2 HN
N
N
N
F
N
N
NH
NH2 N
O
O
N
N
F
N
N
NH
O
NH
S
O
O
O
F
Cl
O
NH
O
NN
NH
N
N
O
Cl
03Q
O
N
NN
NH
N
O
F
F
F
Cl
OH
TAK-285
O
HN
OH
N
NN
NH
O
F
F
F
Cl
Approved drug for lung and breast cancers
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EGFR-TKIs and ErbB2-TKIs
N
N
NH
ON
O
O
F
Cl
Gefitinib
N
N
NH
ON
O
O
F
Cl
Erlotinib
N
N
NH
O
NH
S
O
O
O
F
Cl
Lapatinib
O
NH
N
NO
N
NH
O
N
Cl
Neretinib
0UN
O
NH
O
NN
NH
N
N
O
Cl
EGFR-TKIs
Dual-TKIs (binding with EGFR and/or ErbB2)
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EGFR-TKIs and ErbB2-TKIs
Hydrazone
N
N
NH
NH2 HN
N
N
N
F
Oxime inhibitor
N
N
NH
NH2 N
O
O
N
N
F
03Q
O
N
NN
NH
N
O
F
F
F
Cl
OH
TAK-285
O
HN
OH
N
NN
NH
O
F
F
F
Cl
N
N
HN
NH
N
N
AEE788
Dual-TKIs (binding with EGFR and/or ErbB2)
15
Docked-score chart
HydrazoneN
N
NH
NH2 HN
N
N
N
F
Oxime inhibitor
N
N
NH
NH2 N
O
O
N
N
F
Lapatinib
N
N
NH
O
NH
S
O
O
O
F
Cl
16
Conclusions The post-docking analysis suggested that all
ligands can bind tightly into ATP-binding pocket of ErbB members and can bind to some tyrosine kinase proteins
(JAK2, KDR, PDGFRa, HCK, BLK, TYRO3, EphA2, EphA3, EphA5, EphA10, EphB4, IRR, INSR, ROS, RYK, ABL2, ZAP70, FGFR1, FGFR3, FGFR4 and TYK2~b).
However, they cannot form strong interaction with the binding site of TIE, FES, FAK and SuRTK106 families.
17
Conclusions Because of their low specificity, pyrrolotriazine
inhibitors can bind to the binding sites of many PTKs.
Interestingly, one of the EGFR-HER2 dual inhibitors, lapatinib, can bind to activation site of most SRC family members.
Hydrazone
N
N
NH
NH2 HN
N
N
N
F
Oxime inhibitor
N
N
NH
NH2 N
O
O
N
N
F
18
Benefits Be able to apply this protocol to predict the
binding affinity of the other small molecules among human tyrosine kinases with rapid and efficient
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Further plans Implement inhibitors of the other tyrosine
kinase families to observe the selectivity profile
Improve the protocol for applying with the set of in silico screened compounds targeted to EGFR-TK
Acknowledgements
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Institute of Food Research and Product Development
Laboratory of Protein Engineering and Modeling, Department of Biochemistry, Faculty of Science, Kasetsart University Assist. Prof. Kiattawee Choowongkomon Mr. Adisak Ongsawas Miss Wannarat Yim-Im
Acknowledgements: Computing Resources
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Laboratory of Protein Engineering and Modeling, Department of Biochemistry, Faculty of Science, Kasetsart University
National Center of Excellence in Petroleum, Petrochemical Technology and Advanced Materials, Department of Chemistry, Faculty of Science, Kasetsart University
The National Nanotechnology Center (NANOTEC), the National Science and Technology Development Agency (NSTDA), Thailand
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Thank you for Your Attention