Principles governing the binding of a class of non-peptidic inhibitors to the SH2 domain of src studied by X-ray analysis.
Article Details
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Lange G, Lesuisse D, Deprez P, Schoot B, Loenze P, Benard D, Marquette JP, Broto P, Sarubbi E, Mandine E
Principles governing the binding of a class of non-peptidic inhibitors to the SH2 domain of src studied by X-ray analysis.
J Med Chem. 2002 Jul 4;45(14):2915-22.
- PubMed ID
- 12086479 [ View in PubMed]
- Abstract
A total of 11 structures of the (pp60)src SH2 domain with non-peptidic inhibitors based on the same two closely related inhibitor scaffolds were determined using X-ray crystallography. Surprisingly, the inhibitors that have an IC(50) value between 4 and 2700 nM bind in three different binding modes. Structure comparisons show that the inhibitors aim to maximize the interaction between the hydrophobic substituent and the hydrophobic pY+3 pocket. This is achieved either by an alternative binding mode of the phenyl phosphate or by including water molecules that mediate the interaction between the inhibitor scaffold and a rigid surface of the SH2 domain. The combination of the rigid pY+3 pocket and the rigid protein surface to which the scaffolds bind results in severe distance and angular restraints for putative scaffolds and their substituents. The X-ray data suggest that these restraints seem to be compensated in our system by including water molecules, thereby increasing the flexibility of the system.
DrugBank Data that Cites this Article
- Binding Properties
Drug Target Property Measurement pH Temperature (°C) Paratoulene phosphate Proto-oncogene tyrosine-protein kinase Src IC 50 (nM) 9 N/A N/A Details RU82209 Proto-oncogene tyrosine-protein kinase Src IC 50 (nM) 5 N/A N/A Details RU83876 Proto-oncogene tyrosine-protein kinase Src IC 50 (nM) 2000 N/A N/A Details RU84687 Proto-oncogene tyrosine-protein kinase Src IC 50 (nM) 0.25 N/A N/A Details RU85053 Proto-oncogene tyrosine-protein kinase Src IC 50 (nM) 450 N/A N/A Details