// Apo → Holo cross-validation

Find the drug pocket in the empty structure

We gave the pipeline only the ligand-free apo FMN riboswitch (PDB 6WJR) — no drug, no hints. From the empty structure it recovered half of the true FMN contact residues (9 of 18); the detected pocket centroid lands 2.7 Å from the FMN centroid in the holo co-crystal (PDB 3F2Q) — and 0.63 Å from the nearest ligand atom. The FMN riboswitch is a real antibacterial drug target — the same pocket Merck’s ribocil binds.

Rotate the apo structure yourself

Cartoon backbone of the ligand-free apo structure (PDB 6WJR). Orange: the pocket we detected — it lands on the FMN site. Cyan: the real FMN drug, superposed in from the holo co-crystal (PDB 3F2Q). Red: the cavity off-the-shelf druggability scoring ranks #1 — ~12 Å from any drug. Legend shows each pocket’s cross-conformer persistence.

// Curated angle

The real FMN drug (green) sitting inside the pocket our pipeline detected (orange) from the ligand-free apo structure.

Orange: the pocket our pipeline detected from the apo structure alone. Green: the real FMN drug, superposed in from the holo co-crystal. It lands inside the detected pocket.

50%
strict residue recovery
9 of 18 FMN contact residues
2.7 Å
pocket centroid → FMN centroid
0.63 Å to nearest ligand atom
2.46 Å
apo ↔ holo backbone RMSD
same fold, valid overlay
apo-only
input was the empty structure
ligand never seen by the pipeline

// Why off-the-shelf scoring fails on RNA

The standard druggability score points at the wrong cavity

fpocket’s druggability score is a protein-trained classifier. On this RNA it scores a decoy cavity at 0.75 — and the real FMN drug site at 0.01. Taken at face value it would send a discovery team ~12 Å away from any drug, to the wrong face of the molecule.

Our pipeline ignores that score by design and ranks on RNA-applicable geometry instead. The decoy and the true site are highlighted below — orange is the drug site, red is the high-“druggability” decoy.

True FMN drug site (orange) versus the high-druggability decoy cavity (red), on opposite faces of the apo riboswitch.

// How to read this result

  • This is a detection cross-validation, not a ranking benchmark. It measures how close our detected pocket lands to a known drug site when we start from the empty structure. The locked rank-1 benchmark lives on the methodology page.
  • The drug pocket is detected, but it is not our top-ranked cavity here. Riboswitches are induced-fit — the pocket is only fully formed once the ligand is bound — so in the apo ensemble it is transient (present in 2 of 5 conformers). Our persistence ranker correctly reports it as sub-dominant. We do not present this as a rank-1 result.
  • The structures. Apo input: PDB 6WJR. Holo ground truth: PDB 3F2Q. Both are the same 112-nt FMN riboswitch from Serganov, Huang & Patel, Nature 458:233 (2009).

// Reproduce / inspect

// More worked examples

Seven cleft-binder targets with locked strict@1 / near@1 recovery, including a second FMN riboswitch (5C45) as a benchmark cell.

All worked examples →