Abstract
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 19F 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.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Alcohol Oxidoreductases / antagonists & inhibitors*
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Alcohol Oxidoreductases / metabolism
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Amides / chemical synthesis
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Amides / chemistry*
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Amides / metabolism
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Crystallography, X-Ray
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Drug Discovery
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Drug Stability
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Enzyme Inhibitors / chemical synthesis
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Enzyme Inhibitors / chemistry*
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Enzyme Inhibitors / metabolism
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Humans
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Ligands
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Magnetic Resonance Spectroscopy
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Microsomes, Liver / metabolism
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Molecular Structure
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Protein Binding
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Structure-Activity Relationship
Substances
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Amides
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Enzyme Inhibitors
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Ligands
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Alcohol Oxidoreductases
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sepiapterin reductase