Tc-43/SMARCA2_VHL_MolecularGlue_Designs_6HAY
SMARCA2–VHL Molecular Glue Designs (PDB 6HAY) 884 small molecules generated de novo by the Technetium TC-43.ai engine (GA-II), conditioned on the SMARCA2 bromodomain–VHL interface of the ternary complex 6HAY (2.24 Å), so that one molecule spans both partners. Each molecule was constructed against this pocket rather than selected from a compound library — docking (AutoDock Vina) came afterwards, to place and score the generated molecules in the site. Each is supplied as a… See the full description on the dataset page: https://huggingface.co/datasets/Tc-43/SMARCA2_VHL_MolecularGlue_Designs_6HAY.
SMARCA2–VHL Molecular Glue Designs (PDB 6HAY)
884 small molecules generated de novo by the Technetium `TC-43.ai` engine (GA-II), conditioned on the SMARCA2 bromodomain–VHL interface of the ternary complex [6HAY](https://www.rcsb.org/structure/6HAY) (2.24 Å), so that one molecule spans both partners. Each molecule was constructed against this pocket rather than selected from a compound library — docking (AutoDock Vina) came afterwards, to place and score the generated molecules in the site. Each is supplied as a complete protein–ligand complex.
Molecules were generated by the Technetium `TC-43.ai` engine (GA-II generation). Structural analysis, interface characterisation and dataset curation were performed with Claude Code.
Why this target
SMARCA2 (BRM) is a synthetic-lethal target in SMARCA4 (BRG1)-deficient cancers — roughly 10% of non-small-cell lung cancers and a range of other solid tumours. Because the two paralogues are highly similar, degradation has proven a more tractable strategy than inhibition, and 6HAY is the structural basis for that approach: it captures the SMARCA2<sup>BD</sup>–PROTAC–VHL:ElonginC:ElonginB ternary complex formed by ACBI1.
These designs take the molecular glue route to the same ternary complex — single, compact molecules that occupy the interface rather than bivalent degraders that tether across it.
Not PROTACs — measured, not assumed
The reference ligand in 6HAY (FX8 / ACBI1, MW 918) is a bivalent PROTAC. These designs are not, and the distinction is measurable from the deposited coordinates:
In most designs the two contact sets overlap (median 1–3 shared atoms). These are interface-spanning glues.
Interface engagement
Every design was scored for contacts (≤ 4.5 Å) against both proteins of the ternary complex.
Recurring SMARCA2 pocket: Val1408, Phe1409, Gln1411, Leu1412, Pro1413, Leu1418, Tyr1421, Val1429, Asp1430, Leu1456, Ala1460, Phe1463, Asn1464, Ile1470. Recurring VHL rim: Tyr98, Ile109, His110, Tyr112.
Property profile
870 unique SMILES · 834 distinct Murcko scaffolds — near-one-scaffold-per-molecule diversity. 247 designs satisfy MW ≤ 500, cLogP ≤ 5 and HBD ≤ 5.
Two generation sets
The dataset merges two filtered exports, distinguished by the set column.
Set A is larger and more polar with deeper VHL engagement; Set B is more drug-like and sits further into the bromodomain pocket. All values are medians.
Files
Each complex PDB also carries REMARK records with the ligand id, docking energy, generation SMILES, and a 2D↔3D atom index map.
Caveats
- Docking energies are AutoDock Vina scores, not measured affinities, and do not rank ternary-complex cooperativity.
- Poses are docked into a fixed receptor taken from the ACBI1-bound crystal form. Real glues reshape the interface; induced fit is not modelled here.
- No synthesis, no assay. This is a computational design library.
- The receptor retains crystallographic ethylene glycol and formate from 6HAY.
Citation
Receptor: Farnaby et al., Nat. Chem. Biol. 2019 — PDB 6HAY, SMARCA2/VHL ternary complex with ACBI1.
Designs generated with the Technetium TC-43.ai engine; analysis and curation with Claude Code. Released under CC-BY-4.0.