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Papers of the Week

Papers: 29 Jun 2019 - 5 Jul 2019

Pharmacology/Drug Development

2019 Jul 11

J Med Chem



Fragment-Based Discovery of Novel Potent Sepiapterin Reductase Inhibitors.


Alen J, Schade M, Wagener M, Christian F, Nordhoff S, Merla B, Dunkern TR, Bahrenberg G, Ratcliffe P
J Med Chem. 2019 Jul 11; 62(13):6391-6397.
PMID: 31244106.


Genome-wide-association studies in chronic low back pain patients identified sepiapterin reductase as a high interest target for developing new analgesics. Here we used F NMR fragment screening for the discovery of novel, ligand-efficient SPR inhibitors. We report the crystal structures of six chemically diverse inhibitors complexed with SPR, identifying relevant interactions and binding modes in the sepiapterin pocket. Exploration of our initial fragment screening hit led to double-digit nanomolar inhibitors of SPR with excellent ligand efficiency.