A Back-to-Front Fragment-Based Drug Design Search Strategy Targeting the DFG-Out Pocket of Protein Tyrosine Kinases.

ABSTRACT: We present a straightforward process for the discovery of novel back pocket-binding fragment molecules against protein tyrosine kinases. The approach begins by screening against the nonphosphorylated target kinase with subsequent counterscreening of hits against the phosphorylated enzyme. Back pocket-binding fragments are inactive against the phosphorylated kinase. Fragment molecules are of insufficient size to span both regions of the ATP binding pocket; thus, the outcome is binary (back pocket-binding or hinge-binding). Next, fragments with the appropriate binding profile are assayed in combination with a known hinge-binding fragment and subsequently with a known back pocket-binding fragment. Confirmation of back pocket-binding by Yonetani-Theorell plot analysis progresses candidate frag

SUBMITTER: Iwata H 

PROVIDER: S-EPMC4025632 | biostudies-literature | 2012 Apr

REPOSITORIES: biostudies-literature