Selection of fragments for kinase inhibitor design: decoration is key.

摘要: In fragment-based screening, the choice of best suited fragment hit among detected hits is crucial for success. our study, a kinase lead compound was fragmented, hinge-binding motif extracted as core fragment, and minilibrary five similar compounds with fragment-like properties selected from proprietary database. The structures fragments in complex transforming growth factor β receptor type 1 domain were determined by X-ray crystallography. Three different binding modes are observed that depend on position substitution at fragment. influence substituents preferred pose analyzed various computational approaches. We postulate replacement water molecules leads to modes.