Presentation at SIGBIO41 20th March 2015 Peer reviewed paper was published at http://doi.org/10.2197/ipsjtbio.8.14

1. In silico spleen tyrosine kinase inhibitor
screening by chooseLD
Hideaki Umeyama, Biological Science
Mitsuo Iwadate, Biological Science
Y­h. Taguchi, Physics

2. 1.Introduction ­What is spleen tyrosine kinase?­
2. What is chooseLD?
3.Results
4. Conclusion

3. 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.

4. Protein Feature view of SYK
Protein Tyrosine KinaseSH2 domains

5. Previous efforts for identification of SYK inhibitors:
Targeting C­terminal (ATP binding sites):
R406R112
R788
R343
Geahlen RL, Getting Syk: spleen tyrosine kinase as a
therapeutic target. Trends Pharmacol Sci. 2014 ;35(8):414­22.

6. 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.

7. Previous in silico efforts to identify SYK inhibitors:
Li et al, Comput. Biol. Med., 43, pp.395–404 (2013).
→ Compounds based, SVM
Kaur et al,J Mol Graph Model. 39, pp.165­75 (2013).
→ Compounds based, QSAR
Xie et al, Bioorg Med Chem Lett. 19, 1944­9 (2009).
→ Compounds based, QSAR
To our knowledge, no in silico screening studies
considering SYK protein structure...

8. 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 3D­
structure of
protein­ligand
complex

9. ChooseLD successfully identified HBV target drug candidate
compounds
Murakami Y et al, Biochem Biophys Res Comm. 2015, 456:20­8.

10. Advantages:
Making use of information of known ligand compounds
Disadvantages:
If there are no known ligand compounds, difficult
Two sides of coin

11. 3.Results
Tertiary protein structure inference by FAMS
3OZO_A (whole length, but 50% homology) based
3VF8_A (partial length, but 98% homology) based employed→

12. Template ligands:
4DFN_0K1 3FQE_P5C
1XBB_STI
1XBC_STU
3VF8_0JE
3VF9_477
3SRV_S19
4DFL_0K0
3FQH_057
3EMG_685

13. → Fitting to SYK tertiary structure based upon 3VF8_A

14. 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.

15. TOP 5 ligand candidate compounds by chooseLD
2nd
: Imatinib: Known anti­cancer drug
3rd
, 4th
: Known SYK inhibitors

16. 25th
Nilotinib
Nilotinib
(kinase inhibitor)
SYKの発現にはNilotinib耐性
が必要という既報あリ
（Gioia et al, Blood, 2011)

17. 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.

18. FPA Scores
Log 10
Ki Ki
Pearson: ­0.58
(P=0.0278)
Spearman: ­0.58
(P=0.0300)

19. 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

20. 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