---
license: cc-by-4.0
pretty_name: FKBP12 F36V Binder Designs (PDB 1BL4)
task_categories:
- tabular-regression
- graph-ml
- other
size_categories:
- n<1K
configs:
- config_name: default
  data_files:
  - split: train
    path: designs.csv
language:
- en
tags:
- chemistry
- biology
- drug-discovery
- FKBP12
- FKBP1A
- FKBP
- F36V
- FKBP12-F36V
- P62942
- immunophilin
- PPIase
- peptidyl-prolyl-isomerase
- bump-hole
- bumped-ligand
- chemical-biology
- chemically-induced-proximity
- induced-proximity
- dTAG
- degron
- degradation-tag
- AP1497
- SLF
- synthetic-ligand-of-FKBP
- rapamycin
- FK506
- tacrolimus
- chemical-inducer-of-dimerization
- CID
- molecular-glue
- bifunctional
- heterobifunctional
- PROTAC
- RIPTAC
- targeted-protein-degradation
- protein-protein-interaction
- ternary-complex
- 1BL4
- molecular-docking
- autodock-vina
- protein-ligand-complex
- structure-based-drug-design
- de-novo-design
- generative-design
- generative-ai
- ai-generated
- genetic-algorithm
- GA-II
- synthetic-data
- small-molecule
- SMILES
- SDF
- cheminformatics
- computational-chemistry
- virtual-screening
- TC-43
- technetium
---

# FKBP12 F36V Binder Designs (PDB 1BL4)

**165** de novo, generative-AI–designed small molecules docked into the engineered
**FKBP12 F36V** cavity of **[1BL4](https://www.rcsb.org/structure/1BL4)** (1.9 Å), each
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](https://www.uniprot.org/uniprotkb/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:

| residue | % of poses | | residue | % of poses |
|---|---|---|---|---|
| Trp59 | 100% | | Asp37 | 77% |
| Tyr82 | 100% | | **Val36** | **70%** |
| Ile56 | 100% | | Glu54 | 60% |
| Val55 | 100% | | Phe99 | 47% |
| Tyr26 | 98% | | Ile91 | 27% |
| Ile90 | 95% | | Gln53 | 15% |
| Phe46 | 87% | | Gly28 | 15% |

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

| file | description |
|---|---|
| `designs.csv` | one row per design — 29 columns |
| `ligands.sdf` | all 165 poses, bond orders and formal charges assigned from the SMILES template |
| `receptor_1BL4_FKBP12_F36V.pdb` | chains A + B plus the AP1497 reference ligand |
| `structures/` | 165 complete protein–ligand complexes |

### 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

| | designs (mean) | AP1497 reference |
|---|---|---|
| Vina score | −10.56 (best −12.30) | — |
| ligand efficiency | 0.34 | — |
| molecular weight | 433 | 694 |
| heavy atoms | 31 | 50 |
| cLogP | 3.17 | 5.99 |
| TPSA | 87.6 | 139.3 |
| rotatable bonds | 6.3 | 17 |
| QED | 0.44 | 0.17 |

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.