Dupuytren's disease & drug repurposing

Protein structures

3D models of the proteins behind the drugs and the risk genes, each labelled with what it can and can't tell us.

Why it’s usefulOnly one drug here has actually been seen gripping its target: adalimumab. The other models are useful background, and the labels show where the evidence stops.

A drug–target complex is shown only where the target is well established and an experimental structure exists. Here that is true of just one candidate.

PDB 3WD5 · about 0.5 MB · drag to rotate, pinch or scroll to zoom

TNF (chain A) Adalimumab heavy chain (H) Adalimumab light chain (L)

Experimental structure · drug bound to target

Adalimumab bound to TNF

Source: RCSB PDB 3WD5 PMID 23943614
Method: X-ray diffraction, 3.10 Å
Contents: Human TNF (chain A, 157 residues) with the adalimumab Fab fragment: light chain L (213) and heavy chain H (219)

This is the only candidate on the shortlist whose interaction with its target has been solved experimentally, and the only one tested on its own as a disease-modifying therapy in Dupuytren's PMID 35949922.

What it does not show. It shows how the drug grips TNF, not whether blocking TNF changes Dupuytren's disease. That is a clinical question, answered only partly by a 12-month surrogate endpoint and contradicted in part by evidence that anti-TNF does not reduce collagen accumulation PMID 40337865. At 3.10 Å, side-chain positions at the interface are less certain than the backbone, and this is the Fab fragment, not the full antibody.

And the two leads?

Pirfenidone has no defined molecular target: ChEMBL lists its mechanism as "Unknown", and it has no entries in the PDB. No complex was modelled, because there is nothing established to model it against. Metformin has structures only with its transporters, not with its proposed target.

Context structures Labelled for what they are not

The other six structures are shown as context, each with its limits beside it. None of them shows a drug bound to the protein it is meant to act on.

AlphaFold confidence (pLDDT) Very high >90Confident 70–90Low 50–70Very low <50