Tiny fragment of a vessel-tightening hormone (LDIW / CHEMBL263295)
A four-piece snippet of endothelin-1, the body's own blood-vessel-tightening signal, used only as a lab tool to study how it docks onto its receptor, not a drug.
A researcher, an agent, or an algorithm wrote down the sequence and picked a target to hit.
An AI model like OpenFold3 or AlphaFold built a 3D structure and scored how well it fits the binding site.
A second contributor repeated the computation on their own hardware and the scores matched.
A chemistry service or a researcher ordered the sequence, it was manufactured, and mass spectrometry confirmed the right molecule was produced.
A binding or activity measurement confirmed that it actually does what the computer predicted — or didn't.
What this is
This card describes a four-residue research peptide (LDIW) catalogued in ChEMBL as CHEMBL263295 and reported as a weak ligand at the endothelin type-A receptor (EDNRA), with a measured IC50 of 200 nM. It is not a drug, a clinical candidate, or a marketed compound — it is a small fragment from a medicinal-chemistry series exploring how short pieces of the endothelin-1 C-terminal tail interact with the endothelin receptors. The parent series was designed and characterized at Parke-Davis in the early 1990s (Cody et al., Journal of Medicinal Chemistry, 1995).
The sequence LDIW corresponds to Leu-Asp-Ile-Trp, which maps onto positions 17, 18, 19 and 21 of endothelin-1 — the C-terminal end of the natural hormone that the lead hexapeptide antagonist PD 142893 (Ac-DDip-Leu-Asp-Ile-Ile-Trp) was built around.
History
Endothelin-1 is a 21-residue vasoconstrictor peptide whose minimal biologically active fragment is the C-terminal hexapeptide His¹⁶-Leu¹⁷-Asp¹⁸-Ile¹⁹-Ile²⁰-Trp²¹ — the segment that retains receptor-binding activity in tissue assays even after the disulfide-bridged N-terminal head is removed. In the early 1990s, medicinal chemists at Parke-Davis (Warner-Lambert) used that hexapeptide as a starting scaffold for endothelin receptor antagonists, replacing the imidazole-bearing His16 with bulky non-natural aromatic residues. That work produced PD 142893 (Ac-DDip¹⁶-Leu-Asp-Ile-Ile-Trp²¹), a low-nanomolar combined ETA/ETB antagonist (Cody et al., J. Med. Chem., 1995).
The Cody (1995) paper systematically truncated, methylated, and substituted that hexapeptide to map which residues mattered for binding and which could be moved to push selectivity toward ETB. The LDIW tetrapeptide entered ChEMBL as one of the SAR data points generated in that programme — a fragment characterizing how much affinity remains when the N-terminal cap (Ac-DDip) and one of the two internal isoleucines are removed.
What it does
In the original receptor-binding assays, LDIW competes weakly with radiolabelled endothelin for binding at EDNRA, with a reported IC50 of about 200 nM (ChEMBL CHEMBL263295). That is roughly two-to-three orders of magnitude weaker than the parent hexapeptide PD 142893 — consistent with the broader SAR finding that the N-terminal acetylated bulky-aromatic cap and the full Ile-Ile spacer contribute substantial binding energy to the series.
There is no record of LDIW having been advanced into functional assays, animal models, or clinical work. Its role in the literature is as a SAR data point, not as a drug candidate.
Mechanism
EDNRA is a G-protein-coupled receptor expressed on vascular smooth-muscle cells, the heart, kidney and several neuronal populations. It signals primarily through Gαq/11, activating phospholipase C and triggering calcium release and the long-lasting vasoconstriction that defines endothelin-1's physiology (Davenport et al., reviewed in J. Biochem., 2023). Antagonists at EDNRA are clinically validated in pulmonary arterial hypertension (bosentan, ambrisentan, macitentan), but those are small molecules — not peptides — and the peptide series from which LDIW is drawn never produced an approved drug.
The Cody (1995) SAR study established that, within the C-terminal hexapeptide scaffold, the free C-terminal carboxylate, the L-configured Trp21, the Asp18 side-chain carboxylate and the Leu17 backbone are each essential for activity at the endothelin receptors. LDIW retains all four of these elements but loses the N-terminal cap and one of the two isoleucines — which the published SAR predicts will cost most of the binding affinity, matching the measured 200 nM IC50.
Evidence
- Human: No human trials. No registered clinical trials on ClinicalTrials.gov for this sequence or for CHEMBL263295.
- Animal: No animal-model data published for the LDIW tetrapeptide specifically. The parent hexapeptide series (PD 142893, PD 145065, PD 156252) was characterized in rat and rabbit vascular preparations.
- In vitro: IC50 = 200 nM at EDNRA in a receptor-binding assay, reported as one entry in the Cody et al. (1995) SAR series (ChEMBL CHEMBL263295).
Regulatory status
- US: No regulatory status. LDIW is a research-grade peptide catalogued in ChEMBL; it has not been the subject of an IND, NDA or any FDA filing.
- EU: No EMA filings.
- WADA: Not specifically listed. The peptide is not an endothelin agonist and does not fall within the prohibited peptide-hormone categories.
Related peptides
This card sits in the broader endothelin receptor antagonist series derived from the endothelin-1 C-terminal hexapeptide. Related compounds in that lineage (PD 142893, PD 145065, PD 156252) and the structurally distinct cyclic-pentapeptide ETA-selective antagonists (BQ-123, BE-18257B) are not currently catalogued as individual cards on Peptidopedia. Approved small-molecule EDNRA antagonists used clinically in pulmonary arterial hypertension (bosentan, ambrisentan, macitentan) are non-peptide drugs and are out of scope for the peptide catalog.
▸full evidence table1 metrics
| metric | value | tool |
|---|---|---|
| IC50 | 200 nM | GPCRDB/ChEMBL |
▸structural qualityopenfold3
| metric | value | note |
|---|---|---|
| gpde | 0.787 | global PDE — lower = better |
| disorder | 0.246 | fraction disordered |
| chain pair ipTM (A, B) | 0.876 | interface quality |
▸3-letter notation
▸recipeopenfold3-mlx 0.3.1
| parameter | value |
|---|---|
| model | openfold3-mlx 0.3.1 |
| weights | aedd8f3eb814e392… |
| hardware | apple_m4_base_16gb |
| mlx version | 0.31.1 |
| python | 3.14.3 |
| random seed | 42 |
| msa strategy | colabfold |
| diffusion samples | 1 |
| runtime | 314s |
| predicted by | mlx@peptide |
| predicted at | 2026-04-23 |
python3 openfold3/run_openfold.py predict --query_json {query.json} --runner_yaml examples/example_runner_yamls/mlx_runner.yml --output_dir {output_dir} --num_diffusion_samples 1 ▸citationbibtex
@peptide{pep10317,
sequence = {LDIW},
target = {ednra},
author = {peptidemodel},
year = {2026},
status = {bioassayed}
}