Fragment-Based Discovery of Novel Potent Sepiapterin Reductase Inhibitors

Area of Science:

• Biochemistry
• Medicinal Chemistry
• Pharmacology

Background:

• Chronic low back pain is a significant health issue.
• Genome-wide association studies highlight sepiapterin reductase (SPR) as a key target for novel analgesic development.

Purpose of the Study:

• To discover novel, ligand-efficient inhibitors of sepiapterin reductase (SPR) using fragment-based screening.
• To characterize the binding interactions and modes of diverse SPR inhibitors through structural analysis.

Main Methods:

• Utilized 19F NMR fragment screening to identify initial SPR inhibitor hits.
• Determined crystal structures of six chemically diverse inhibitors bound to SPR.
• Analyzed inhibitor interactions within the sepiapterin binding pocket.

Main Results:

• Identified novel, chemically diverse inhibitors of sepiapterin reductase.
• Reported six crystal structures revealing key interactions and binding modes.
• Optimized initial fragment screening hits into double-digit nanomolar SPR inhibitors with high ligand efficiency.

Conclusions:

• Fragment-based screening is effective for discovering potent SPR inhibitors.
• Structural insights guide the development of novel analgesics targeting sepiapterin reductase.
• The identified inhibitors represent promising leads for chronic low back pain therapeutics.