Blood-vessel-relaxing peptide (CHEMBL94983 / DIIW)
A tiny lab-made peptide that blocks the body's blood-vessel-tightening signal, which could lower blood pressure; used only as a lab research tool.
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
CHEMBL94983 is a short research peptide — just four amino acids (Asp-Ile-Ile-Trp, written as DIIW) — built to block the endothelin-A receptor (EDNRA, also called ET~A~). The endothelin-A receptor sits mainly on vascular smooth muscle, where it drives powerful, sustained blood-vessel constriction when activated by endothelin-1. This compound was synthesised as part of structure-activity work aimed at finding minimal peptide sequences capable of antagonising that receptor, and carries an IC50 of 13.0 nM at EDNRA in a binding assay (ChEMBL CHEMBL94983). The stored four-residue sequence DIIW represents only the canonical C-terminal core; the ChEMBL compound additionally bears an N-terminal modification preceding that core, placing it in the same chemical family as the Parke-Davis hexapeptide antagonist PD 142893 (Ac-D-Dip-Leu-Asp-Ile-Ile-Trp).
History
The four residues Asp18-Ile19-Ile20-Trp21 form the C-terminal half of endothelin-1's own C-terminal hexapeptide (His16-Leu17-Asp18-Ile19-Ile20-Trp21). This hexapeptide region was identified early on as the minimum structural motif needed to develop antagonist activity at both endothelin receptor subtypes. Researchers at Parke-Davis (Warner-Lambert) — led by Cody and colleagues — mapped the structure-activity landscape of this hexapeptide scaffold and demonstrated that substitution of the N-terminal His16 position with bulky non-natural D-amino acids (such as 3,3-diphenylalanine, Dip) converted an agonist fragment into a potent, low-nanomolar antagonist. Their landmark 1995 paper in the Journal of Medicinal Chemistry fully described PD 142893, the prototype dual ETA/ETB antagonist built on the Asp-Ile-Ile-Trp core, and showed how further N-terminal variation could shift selectivity toward the ETB subtype (Cody and colleagues, Journal of Medicinal Chemistry 1995). The DIIW compound catalogued here (CHEMBL94983) represents one analogue from that SAR series, retaining the canonical C-terminal pharmacophore with N-terminal modifications that alter its receptor subtype selectivity profile.
What it does
The compound occupies the EDNRA binding site, blocking endothelin-1 from activating it. When endothelin-1 binds unobstructed to EDNRA on vascular smooth muscle, it triggers a sustained vessel-wall contraction that raises blood pressure and vascular resistance. By occupying the same binding pocket without activating the receptor, DIIW-core antagonists suppress that vasoconstrictive signal. The C-terminal Trp21 residue and the adjacent Ile-Ile pair are key contacts in the receptor's transmembrane pocket; structure-activity data show that removal or replacement of these residues substantially reduces binding potency, confirming that the DIIW tetrapeptide carries the central pharmacophoric elements of the broader PD 142893 antagonist scaffold (Cody and colleagues, Journal of Medicinal Chemistry 1995).
Evidence
- Human: No clinical data. Research-tool compound only; no registered trials.
- Animal: No in vivo data available for this specific tetrapeptide. Closely related hexapeptides in the PD 142893 series were functional antagonists of endothelin-stimulated vasoconstriction in animal preparations, both in vitro and in vivo (Cody and colleagues, Journal of Medicinal Chemistry 1995).
- In vitro: IC50 = 13.0 nM at EDNRA (ChEMBL bioassay, CHEMBL94983). Hexapeptide predecessors in this SAR series demonstrated low nanomolar affinity for both ETA and ETB receptor subtypes in radioligand displacement assays (Cody and colleagues, Journal of Medicinal Chemistry 1995).
Mechanism
EDNRA is a class A G-protein-coupled receptor that couples principally to Gq/G11, activating phospholipase C and generating inositol-1,4,5-trisphosphate and diacylglycerol. These second messengers mobilise intracellular calcium, producing the smooth-muscle contraction responsible for endothelin-1's long-lasting vasopressor effect. The receptor also carries mitogenic activity. Endothelin-1 and endothelin-2 are equipotent at EDNRA, while endothelin-3 shows roughly 100-fold lower affinity (IUPHAR/BPS Guide to Pharmacology, family 21).
The C-terminal region of endothelin-1 (Asp18–Trp21) inserts into the transmembrane binding pocket, and the terminal tryptophan is essential for receptor activation. Antagonist peptides derived from the same C-terminal sequence occupy this pocket without triggering the conformational changes required to activate downstream signalling. The DIIW core corresponds precisely to this Asp18-Ile19-Ile20-Trp21 region, and the SAR literature confirms that both the Ile-Ile pair and the terminal Trp are indispensable for nanomolar potency at EDNRA (Cody and colleagues, Journal of Medicinal Chemistry 1995).
Regulatory status
- US / EU: No regulatory status. Research-tool compound; not approved and not in clinical development.
- WADA: Not listed.
Related peptides
CHEMBL94983 derives from the same hexapeptide scaffold as PD 142893, the prototypical dual ETA/ETB peptide antagonist used to characterise endothelin receptor subtypes in the early 1990s. Non-peptide small-molecule antagonists at the same EDNRA target went on to reach clinical approval: bosentan (dual ETA/ETB) in 2001, ambrisentan (ETA-selective) in 2007, and macitentan (dual ETA/ETB) in 2013, all indicated for pulmonary arterial hypertension. The peptide scaffold of CHEMBL94983 is a research ancestor to that therapeutic lineage, though it was not itself advanced clinically due to the limited oral bioavailability typical of hexapeptide-class compounds.
▸full evidence table1 metrics
| metric | value | tool |
|---|---|---|
| IC50 | 13 nM | GPCRDB/ChEMBL |
▸structural qualityopenfold3
| metric | value | note |
|---|---|---|
| gpde | 0.792 | global PDE — lower = better |
| disorder | 0.246 | fraction disordered |
| chain pair ipTM (A, B) | 0.862 | 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 | 312s |
| 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{pep10329,
sequence = {DIIW},
target = {ednra},
author = {peptidemodel},
year = {2026},
status = {bioassayed}
}