DeCure's autonomous Rare AI scientist is researching a drug-repurposing hypothesis for dihydropteridine reductase deficiency — screening already-approved drugs against its 1-gene Open Targets disease module to publish open-access research. Research is fast; the path to publication is funded in milestone stages.
Disease moduleDihydropteridine reductase deficiency maps to a 1-gene Open Targets module — the target space DeCure's AI scientist screens approved drugs against.
DeCure.ai methodSignature reversal (LINCS) plus network proximity (STRING) rank already-approved drugs likely to perturb this module — the same engine that produces DeCure.ai's repurposing hypotheses.
Repurposing thesisScreening approved medicines against this disease module, then publishing the evidence for the strongest candidate. Known pharmacology and human exposure data make the first question sharper — they do not establish safety or efficacy in a new indication.
Research record
01
ResearchComing soon
Candidate research + dossier — target rationale, drug-repurposing thesis and evidence pack.proof: Published dossier + on-chain hash
02
ValidationComing soon
In-vitro biological validation at a contract research org (CRO).proof: CRO contract + in-vitro report
03
Peer review & paperComing soon
Peer-reviewed paper published open-access (preprint + journal).proof: DOI + open-access link + on-chain hash
Current lead
approvedTetrahydrobiopterinApproved drug
Structures already discussed alongside dihydropteridine reductase deficiency in the retrieved literature, rendered from public PubChem SMILES. Which drugs appear here reflects the evidence found, not a ranked prediction.
Molecular view
BOVINE ENDOTHELIAL NITRIC OXIDE SYNTHASE HEME DOMAIN — Tetrahydrobiopterin has a real, experimentally solved structure in complex with this target (PDB 1D1V, 1.93 Å). This is the drug's own deposited structure, not a prediction, and confirms it is a structurally characterised molecule rather than an untested guess.
Loading structure…
helix sheet h4bdrag to rotate · scroll to zoom
RCSB Protein Data Bank · entry 1D1V · 1.93 Å · ligand Tetrahydrobiopterin (H4B). Experimental structure, not a prediction.
What the evidence adds up to
Dihydropteridine reductase deficiency is one of two inherited defects that cause tetrahydrobiopterin deficiency in hyperphenylalaninaemic infants. A 1984 screening method using blood spots on Guthrie cards can identify the deficiency positively; a biopterin value of less than 6.0 micrograms per litre in the presence of hyperphenylalaninaemia indicates further investigation for the other defect, dihydrobiopterin synthesis deficiency.
A 1986 study correlated response to a tetrahydrobiopterin (BH4) load with the type of mutation in dihydropteridine reductase deficient patients. Four patients without mutant dihydropteridine reductase molecules in their cells responded to the BH4 load, whereas three patients with mutant dihydropteridine reductase in their cells did not respond. Intravenous injection of BH4 in one of the non-responding cases again showed no response.
The crystallographic structure of a human dihydropteridine reductase NADH binary complex was solved in 1993 using 2.5 Å data refined to an R value of 16.9%, representing the first complete structural characterisation of this human enzyme. The enzyme itself, which catalyses the reduction of quinoid dihydropteridines in the presence of NADH or NADPH, was purified approximately 800-fold from rat liver tissue in 1972, and its specificity and inhibition by some 2,4-diaminopteridines were studied. A 1996 study found that dihydropteridine reductase activity can be affected by either chemotherapeutics or by pathological conditions in several haematological malignancies, Behcet's disease, rheumatoid arthritis and familial Mediterranean fever, but did not address the deficiency directly.
What is still missing is any clinical trial data for treatment of dihydropteridine reductase deficiency itself, beyond the small 1986 patient series showing BH4 non-responsiveness in those with mutant protein. No therapy has been tested in a controlled setting, and patient stratification by mutation type has not been translated into a treatment protocol. Funding for drug development or repurposing screening in this ultra-rare disorder remains absent.
Evidence
Retrieved by DeepSearch across 234,678,978 indexed works and resolved on OpenAlex — ranked by citations, including the results that did not work.
Archives of Disease in Childhood · 1984 · 39 citations · open access
Blood spots on Guthrie cards can be used for inherited tetrahydrobiopterin deficiency screening in hyperphenylalaninaemic infants.
AbstractWe describe a method of screening for dihydropteridine reductase deficiency and dihydrobiopterin synthesis deficiency--the two inherited defects that cause tetrahydrobiopterin deficiency--using blood spots on Guthrie cards. Dihydropteridine reductase deficiency may be identified positively, and a biopterin value of less than 6.0 micrograms/l in the presence of hyperphenylalaninaemia indicates further investigation for dihydrobiopterin synthesis deficiency.
The crystallographic structure of a human dihydropteridine reductase NADH binary complex expressed in Escherichia coli by a cDNA constructed from its rat homologue.
AbstractA human dihydropteridine reductase (EC 1.6.99.10) has been created from a rat cDNA clone by a single five-oligonucleotide mutagenesis reaction and expressed in good yield in Escherichia coli. The enzyme has been purified to homogeneity, and kinetic identity to the naturally occurring enzyme has been proven. Crystallization has also been achieved, and the crystal structure was solved using 2.5 A data that was refined to an R value of 16.9%. The structure described in this report represents the first complete structural characterization of this important human enzyme.
European Journal of Biochemistry · 1972 · 25 citations · open access
Dihydropteridine Reductase
AbstractDihydropteridine reductase, which catalyses the reduction of quinoid dihydropteridines in the presence of NADH or NADPH, has been purified approximately 800‐fold from rat liver tissue. The specificity of the purified dihydropteridine reductase with respect to quinoid dihydropteridine has been studied, by comparing the Michaelis constants and maximum velocity in systems containing the same concentration of enzyme. In addition, the inhibitory effect of some 2,4‐diaminopteridines has been studied. Furthermore the present work shows, that the quinone reductase activity observed with a previously used dihydropteridine reductase preparation is attributable to the presence of a quinone reductase in this preparation.
Journal of Inherited Metabolic Disease · 1986 · 24 citations
Tetrahydrobiopterin non‐responsiveness in dihydropteridine reductase deficiency is associated with the presence of mutant protein
AbstractCorrelation of the response to a load of tetrahydrobiopterin (BH4) in dihydropterin reductase (DHPR) deficient patients to the type of mutation in these patients has led to the conclusion that 4 patients without mutant DHPR molecules in their cells respond to the BH4 load, whereas 3 patients with mutant DHPR in their cells do not respond. Intravenous injection of BH4 in 1 of the cases not responding to BH4 again showed no response.
Pharmacy and Pharmacology Communications · 1996 · 1 citations
The Change in Dihydropteridin Reductase Activity in Some Diseases
AbstractDihydropteridin reductase (EC 1.6.99.7) is an essential enzyme in the maintenance of tetrahydrobiopterin, which is a natural cofactor for nitric oxide synthase, alkyl glycerylmonooxygenase, and biosynthesis of catecholamines and 5-HT. The study was undertaken to evaluate dihydropteridin reductase activity on blood spots from patients with several haematological malignancies, Behcet's disease, rheumatoid arthritis and familial Mediterranean fever.
Our results suggest that dihydropteridin reductase activity can be affected by either chemotherapeutics or by pathological conditions.
Disease module: DeepOracle (Open Targets). Structures: RDKit from PubChem SMILES. Literature: retrieved by DeepSearch across 234,678,978 indexed works (targeted per-candidate search), resolved on OpenAlex.
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