Principles governing the binding of a class of non-peptidic inhibitors to the SH2 domain of src studied by X-ray analysis.

Article Details

Citation

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
DrugTargetPropertyMeasurementpHTemperature (°C)
Paratoulene phosphateProto-oncogene tyrosine-protein kinase SrcIC 50 (nM)9N/AN/ADetails
RU82209Proto-oncogene tyrosine-protein kinase SrcIC 50 (nM)5N/AN/ADetails
RU83876Proto-oncogene tyrosine-protein kinase SrcIC 50 (nM)2000N/AN/ADetails
RU84687Proto-oncogene tyrosine-protein kinase SrcIC 50 (nM)0.25N/AN/ADetails
RU85053Proto-oncogene tyrosine-protein kinase SrcIC 50 (nM)450N/AN/ADetails