Fragment-Based Discovery of Novel Potent Sepiapterin Reductase Inhibitors

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 19 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.

Highly Reactive Cyclic Monoaryl Iodoniums Tuned as Carbene Generators Couple with Nucleophiles under Metal-Free Conditions

“…Taken together, six series of chemical fragments are rapidly built from our developed cMAVIs in two steps. These high-quality fragments are demanded in the drug discovery, especially in the fragment-based approaches ( Alen et al., 2019 ; Heightman et al., 2018 ; Kirsch et al., 2019 ).

Figure 4 DOS Strategy Applied to Construct Heterocyclic Fragments from 1a and 1a-Alike cMAVIs Note: Unless stated, otherwise R, R 1 , and R 2 stand for H; DCE, 1,2-dichloroethane; NBS, N -bromosuccinimide.

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“…Taken together, six series of chemical fragments are rapidly built from our developed cMAVIs in two steps. These high-quality fragments are demanded in the drug discovery, especially in the fragment-based approaches (Alen et al, 2019;Heightman et al, 2018;Kirsch et al, 2019).…”

19F NMR viewed through two different lenses: ligand-observed and protein-observed19F NMR applications for fragment-based drug discovery

“…A recent application of competitive FAXS in fragment-based drug discovery was a screen against sepiapterin reductase, a target in chronic pain. 74 This assay was chosen because the competitive mode allowed the researchers to focus their screen on a substrate binding pocket, and detection of the 19 F signal allowed for the use of large amounts of cosubstrate, NADP/ NADPH. N-Acetylserotonin, a known binder (K d B 5 mM) was fluorinated with a CF 3 moiety, to serve as the spy molecule.…”

Sepiapterin reductase: Characteristics and role in diseases

“…Furthermore, N‐acetylserotonin (NAS), an inhibitor of sepiapterin reductase, could significantly reduce chronic pain in the spared nerve injury model and the paw inflammation model through inhibiting BH 4 production 87 . Therefore, SPR has become a more attractive drug target for chronic pain, and many studies have focused on the development of SPR inhibitors 91,93,94 . In particular, Latremoliere et al 91 developed a new SPR inhibitor—SPRi3—and proved that SPR inhibition was a viable approach for normalizing neuropathic and inflammatory pain hypersensitivity without unacceptable side effects.…”

“…Compared to sulphonamides, the third SPR inhibitors show a higher affinity to human SPR and higher potency in reducing BH 4 synthesis in cells. Recently, using NMR and X‐ray supported fragment screening, Alen et al 93 obtained a new compound with good physicochemical and in vitro ADME properties that could function as a candidate for follow‐up hit‐to‐lead optimization. All of these drugs provide possible therapies for various diseases; however, considering the toxicity and bioavailability of these inhibitors, new inhibitors should be developed.…”