Tc-43/FKBP12_F36V_Binder_Designs_1BL4

FKBP12 F36V Binder Designs (PDB 1BL4)

165 small molecules generated de novo by the Technetium `TC-43.ai` engine (GA-II), conditioned on the engineered FKBP12 F36V bump-hole cavity of [1BL4](https://www.rcsb.org/structure/1BL4) (1.9 Å). 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). Target setup, receptor validation and dataset curation by Claude Code.

Target

FKBP12 (P62942) is a 12 kDa peptidyl-prolyl isomerase and the receptor for FK506 and rapamycin. The F36V mutation enlarges the ligand cavity, creating a "hole" that accepts correspondingly "bumped" synthetic ligands while wild-type FKBP12 does not — the basis of the bump-hole systems used throughout chemically induced proximity, including dTAG degron tagging and heterobifunctional proximity-inducing molecules.

PDB 1BL4 is FKBP mutant F36V complexed with a remodeled synthetic ligand — the reference bumped ligand AP1497 (693.8 Da). The receptor here is the deposited dimer: chains A and B, 107 residues each (mature FKBP12, initiator Met removed, so the mutation sits literally at position 36 and receptor numbering is UniProt − 1). AP1497 is retained in the chain B cavity; the designs occupy the chain A cavity.

Binding site

All 165 designs bind the chain A FKBP cavity. Contact frequencies across the set:

Trp59, Tyr82, Ile56 and Val55 form the invariant floor of the cavity — every pose touches all four.

Val36 engagement — read this before selecting compounds

Val36 is the mutation. It is the only residue that distinguishes this receptor from wild-type FKBP12, so a design that does not contact it has no structural basis for preferring F36V over wild type. Wild-type FKBP12 is one of the most abundant cytosolic proteins in mammalian cells, which makes that distinction the difference between a usable chemical-biology tool and one swamped by the endogenous pool.

• —`val36_contact = True` — 115 of 165 designs (70%). Use this subset where F36V discrimination matters.
• —The remaining 50 bind the conserved cavity floor only and should be treated as generic FKBP12 binders.

This dataset does not include wild-type FKBP12 counter-docking; Val36 contact is a structural proxy, not a measured selectivity.

Contents

Columns

design_id, rank, smiles, pose_smiles, stereo_check, vina_score, ligand_efficiency, mw, clogp, tpsa, qed, hbd, hba, rotatable_bonds, heavy_atoms, rings, aromatic_rings, fsp3, formal_charge, murcko_scaffold, chemotype_cluster, n_contact_residues, contact_residues, val36_contact, min_dist_protein_ang, min_dist_ap1497_ang, steric_clash, ecfp4_similarity_to_ap1497, pose_file

Set characteristics

All 165 SMILES are unique, spanning 142 Murcko scaffolds and 66 chemotypes (Butina on ECFP4 at Tanimoto 0.4), with 46 singletons and a largest cluster of 33.

The designs are chemically independent of the reference. Maximum ECFP4 similarity to AP1497 across the set is 0.19 (mean 0.13), and none of the 165 contains a pipecolate ester — the canonical FKBP-binding motif shared by FK506, rapamycin, SLF and AP1497. The set explores the cavity with different chemistry rather than re-deriving the known pharmacophore. Whether that is an advantage or a liability depends on how much the pipecolate anchor contributes to the binding you need.

Pose quality

Docking was rigid-receptor with a fixed receptor across the whole set (verified: a single set of receptor and AP1497 coordinates in all 165 files). Poses are sterically clean:

• —closest heavy-atom contact to protein: median 2.97 Å (5th–95th percentile 2.67–3.11)
• —only 3 of 165 poses have any atom within 2.5 Å of the protein (steric_clash)
• —zero poses clash with AP1497 in the adjacent chain B cavity
• —all 165 ligands round-tripped 3D pose → bond orders → SMILES with matching connectivity

Scores were pre-filtered upstream at −10.0 kcal/mol, so the set contains nothing above that value and the distribution describes the surviving tail only. Treat scores as a ranking signal, not affinity.

Citation

Molecules generated by the Technetium TC-43.ai engine. Receptor validation and dataset curation by Claude Code. Released under CC-BY-4.0.