A Role for Hydration in Interleukin-2 Inducible T Cell Kinase (Itk) Selectivity.

The selectivity profile of kinase inhibitors is commonly explained in terms of favourable or unfavourable interactions between the inhibitor and active site residues. In practice residue sequence differences have not always been sufficient to explain observed selectivity profiles. A series of interleukin-2 inducible T cell kinase (Itk, EC 2.

Computational analysis of phosphopeptide binding to the polo-box domain of the mitotic kinase PLK1 using molecular dynamics simulation.

The Polo-Like Kinase 1 (PLK1) acts as a central regulator of mitosis and is over-expressed in a wide range of human tumours where high levels of expression correlate with a poor prognosis. PLK1 comprises two structural elements, a kinase domain and a polo-box domain (PBD). The PBD binds phosphorylated substrates to control substrate phosphorylation by the kinase domain.

Understanding kinase selectivity through energetic analysis of binding site waters.

Kinases remain an important drug target class within the pharmaceutical industry; however, the rational design of kinase inhibitors is plagued by the complexity of gaining selectivity for a small number of proteins within a family of more than 500 related enzymes. Herein we show how a computational method for identifying the location and thermodynamic properties of water molecules within a protein binding site can yield insight into previously inexplicable selectivity and structure-activity relationships. Four kinase systems (Src family, Abl/c-Kit, Syk/ZAP-70, and CDK2/4) were investigated, and differences in predicted water molecule locations and energetics were able to explain the experimentally observed binding selectivity profiles.

Identification of ligand binding sites on proteins using a multi-scale approach.

Identification of a ligand binding site on a protein is pivotal to drug discovery. To date, no reliable and computationally feasible general approach to this problem has been published. Here we present an automated efficient method for determining binding sites on proteins for potential ligands without any a priori knowledge.