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In silico spleen tyrosine kinase inhibitor screening by chooseLD
Hideaki Umeyama, Biological ScienceMitsuo Iwadate, Biological Science
Yh. Taguchi, PhysicsChuo University
1.IntroductionWhat is spleen tyrosine kinase?
Spleen tyrosine kinase (SYK):Nonreceptor kinase causing various diseases,
thus has been a drug target.Diseases related to SYK (by gendoo server):
Breast Cancer (P=3.92 x 109)
Arthus Reaction (P=5.09 x 107)
Lymphoma, BCell (P=1.79 x 106)
Neoplasm Metastasis (P=7.67 x 106)
Inflammation (P=8.28 x 105) etc, etc.
Previous efforts for identification of SYK inhibitors:Targeting Cterminal (ATP binding sites):
R406R112
R788R343
Geahlen RL, Getting Syk: spleen tyrosine kinase as a therapeutic target. Trends Pharmacol Sci. 2014 ;35(8):41422.
Targeting SH2 domain
Niimi T et al, Design and synthesis of nonpeptidic inhibitors for the Syk Cterminal SH2 domain based on structurebased insilico screening. J Med Chem. 2001 20; 44(26) :473740.
Previous in silico efforts to identify SYK inhibitors:Li et al, Comput. Biol. Med., 43, pp.395–404 (2013).
→ Compounds based, SVMKaur et al,J Mol Graph Model. 39, pp.16575 (2013).
→ Compounds based, QSARXie et al, Bioorg Med Chem Lett. 19, 19449 (2009).
→ Compounds based, QSAR
To our knowledge, no in silico screening studies considering SYK protein structure...
2. What is chooseLD?
TAKAYA et al, Chem. Pharm. Bull. 56(5) 742—744 (2008)
Inferred tertiary protein structure
Template ligands
Ligand candidate compounds
Predicted 3Dstructure of proteinligand complex
ChooseLD successfully identified HBV target drug candidate compounds
Murakami Y et al, Biochem Biophys Res Comm. 2015, 456:208.
Advantages:Making use of information of known ligand compounds
Disadvantages:If there are no known ligand compounds, difficult
Two sides of coin
3.ResultsTertiary protein structure inference by FAMS3OZO_A (whole length, but 50% homology) based
3VF8_A (partial length, but 98% homology) based employed→
Template ligands:4DFN_0K1 3FQE_P5C
1XBB_STI
1XBC_STU
3VF8_0JE
3VF9_477
3SRV_S19
4DFL_0K0
3FQH_057
3EMG_685
Selection of ligand candidate compounds from DrugBank:
At least with more than 0.25 Tanimoto Index with one of 10 template compounds (see the previous slide)
6583 compounds (in DrugBank) 1043 compounds→
For each of 1024 compounds, 1000 randomly generated 3D structures were tried to aligned to inferred tertiary structure of SYK. Binding structure with the best FPA Scores were employed. Three independent runs were performed. All 1024 compounds were ranked based on mean FPA Scores of three independent trials.
TOP 5 ligand candidate compounds by chooseLD
2nd: Imatinib: Known anticancer drug
3rd, 4th: Known SYK inhibitors
Comparison with known SYK inhibitors listed in ChEMBL
ChooseLD was applied to these compounds and they were tried to bind to inferred tertiary structure of SYK and FPA Scores were computed.
Comparison with SwissDock (*)
Log 10
Ki Ki
dG
Pearson: 0.48(P=0.079)
Spearman: 0.49(P=0.077)
(*) cited by 115 times since 2011 by google scholar
4. Conclusion
In silico discovery of SYK inhibitor was performed by chooseLD.
Top 5 candidates compounds include imanitib (famous anticancer drug) and two know SYK inhibitors.
Performance was tested using known SYK inhibitors listed in ChEMBL and ChooseLD outperformed SwissDock, a frequently cited drug discovery web server.