Günter Hölzemann

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

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

Cyclic RGD peptides with a novel mimetic

The integrins and their ligands regulate a range of cell-cell and cell-matrix interactions. The αv β 3 integrin is expressed on tumor-induced angiogenic blood vessels which makes inhibitors of this receptor valuable tools for therapeutic purposes [1]. A number of cyclic peptides containing the Arg–Gly–Asp(RGD) sequence were reported to be selective inhibitors of this integrin [2]. cyclo(–RGD D -Phe–Val–) [c(RGDfV)], for example, serves as a standard in many biological assays. Whereas the RGD part of the molecule is very sensitive to changes, the remaining two amino acids, D-Phe and Val, were exchanged by a variety of amino acids and building blocks without loosing affinity or selectivity for the αv β3 integrin [3,4]. We have synthesized a substituted 2-(3-aminomethyl-phenylamino)-propionic acid building block and incorporated it into cyclic RGD peptides. The 3-aminomethyl-phenylamine (AMP) residue is similar to the Mamb (m-(aminomethyl)benzoic acid) residue described by A.C. Bach, II, and co-workers [5].