4X2G

Selection of fragments for kinase inhibitor design: decoration is key

Summary for 4X2G

• Entry DOI: 10.2210/pdb4x2g/pdb
• Related: 4X2F
• Descriptor: TGF-beta receptor type-1, 4-[(4-aminophenyl)amino]pyrido[2,3-d]pyrimidin-5(6H)-one, SULFATE ION, ... (5 entities in total)
• Functional Keywords: transferase, protein kinase, inhibitor complex, transferase-transferase inhibitor complex, transferase/transferase inhibitor
• Biological source: Homo sapiens (Human)
• Cellular location: Cell membrane; Single-pass type I membrane protein: P36897
• Total number of polymer chains: 1
• Total formula weight: 35353.61

Authors

Czodrowski, P.,Hoelzemann, G.,Barnickel, G.,Greiner, H.,Musil, D. (deposition date: 2014-11-26, release date: 2015-08-12, Last modification date: 2024-02-28)

Primary citation

Czodrowski, P.,Holzemann, G.,Barnickel, G.,Greiner, H.,Musil, D.
Selection of fragments for kinase inhibitor design: decoration is key.
J.Med.Chem., 58:457-465, 2015

PubMed Abstract: 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.

PubMed: 25437144
DOI: 10.1021/jm501597j

Experimental method

X-RAY DIFFRACTION (1.51 Å)