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J Mol Graph Model. 2017 Aug;75:125-131. doi: 10.1016/j.jmgm.2017.05.007. Epub 2017 May 15.

Promiscuity and selectivity of small-molecule inhibitors across TAM receptor tyrosine kinases in pediatric leukemia.

Author information

1
Department of Pediatrics, Linyi Central Hospital, Yishui 276400, China.
2
Department of Hematology, Linyi Central Hospital, Yishui 276400, China.
3
Department of Neurosurgery, Linyi Central Hospital, Yishui 276400, China.
4
Jinan Maternity and Child Health Care Hospital, Jinan 250001, China. Electronic address: xiaojingzzhang@126.com.

Abstract

The TAM receptor tyrosine kinase family member Mer has been recognized as an attractive therapeutic target for pediatric leukemia. Beside Mer the family contains other two kinases, namely, Tyro3 and Axl, which are highly homologues with Mer and thus most existing small-molecule inhibitors show moderate or high promiscuity across the three kinases. Here, the structural basis and energetic property of selective binding of small-molecule inhibitors to the three kinases were investigated at molecular level. It is found that the selectivity is primarily determined by the size, shape and configuration of kinase's ATP-binding site; the Mer and Axl possess a small, closed active pocket as compared to the bulky, open pocket of Tyro3. The location and conformation of active-site residues of Mer and Axl are highly consistent, suggesting that small-molecule inhibitors generally have a low Mer-over-Axl selectivity and a high Mer-over-Tyro3 selectivity. We demonstrated that the difference in ATP binding potency to the three kinases is also responsible for inhibitor selectivity. We also found that the long-range interactions and allosteric effect arising from rest of the kinase's active site can indirectly influence inhibitor binding and selectivity.

KEYWORDS:

Inhibitor selectivity; Molecular modeling; Pediatric leukemia; TAM kinase

PMID:
28551502
DOI:
10.1016/j.jmgm.2017.05.007
[Indexed for MEDLINE]

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