Blood-vessel-tightening blocker (CHEMBL318020)
A lab-made five-piece mini-peptide that blocks the body switch which tightens blood vessels; used only as a research tool, not a medicine.
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
CHEMBL318020 is a short research peptide designed to block the endothelin receptor — a cell-surface receiver found mainly on blood-vessel walls that, when activated by the natural hormone endothelin-1, drives strong vasoconstriction. It is one of many analogs explored in a 1990s medicinal-chemistry program at Parke-Davis aimed at turning the hydrophobic C-terminal tail of endothelin into a small-molecule-sized drug lead (Cody et al., J. Med. Chem. 1995). The stored sequence here, LDEIW (Leu-Asp-Glu-Ile-Trp), is the standard-letter five-residue core; in ChEMBL the full molecule is recorded as an acetyl-capped hexapeptide with a non-standard hydrophobic residue at the N-terminus, so the raw 5-letter string omits both the acetyl cap and that modified residue. It has no clinical use — it is a tool compound from an exploratory structure-activity series, not a therapeutic.
History
Endothelin-1 was identified in 1988 as the most potent vasoconstrictor known. Its C-terminal hexapeptide (His16-Leu-Asp-Ile-Ile-Trp21) was quickly shown to be the minimum fragment retaining receptor recognition, and groups at several pharmaceutical companies began grafting onto that hexapeptide scaffold to make short antagonist leads. The Parke-Davis program of Cody, Doherty and colleagues was among the most productive, generating the prototype antagonist PD 142893 (Ac-DDip16-Leu-Asp-Ile-Ile-Trp21), where "DDip" is the unnatural amino acid β,β-diphenyl-D-alanine. CHEMBL318020 is one of the many analogs that came out of the surrounding SAR exploration described in Cody et al. (1995), in which residue substitutions across the hexapeptide were systematically tested to map which positions tolerated change and which were essential for ETA versus ETB activity. The peptidic series was eventually superseded by orally bioavailable small molecules — bosentan (FDA-approved 2001), ambrisentan (2007), and macitentan (2013) — all of which target the same two receptors but are not peptides.
What it does
In cell-based assays this compound binds both endothelin receptor subtypes (ETA and ETB) and blocks the downstream signaling that endothelin-1 normally triggers in vascular smooth muscle. The 5-mer stored on this card sits inside the same C-terminal-hexapeptide chemotype as PD 142893 but is substantially weaker than the lead compound — its measured affinities are in the high-nanomolar to low-micromolar range rather than the low-nanomolar range that defines the most potent members of the series (Cody et al., 1995).
Mechanism
The endothelin receptors EDNRA (ETA) and EDNRB (ETB) are class-A G-protein-coupled receptors. ETA sits predominantly on vascular smooth muscle and mediates vasoconstriction; ETB sits on endothelial cells (where it triggers nitric oxide and prostanoid release) and also on smooth muscle. Both receptors couple to multiple G-proteins (Gq, G11, Gs, Gi2) and activate phospholipase C, phospholipase A2, and phospholipase D pathways (IUPHAR/BPS Guide to Pharmacology, endothelin receptors family page). C-terminal endothelin hexapeptides like the PD 142893 series occupy the same hydrophobic pocket that the natural Trp21 of endothelin-1 docks into, but lacking the disulfide-locked N-terminal core of the full 21-residue hormone they cannot trigger receptor activation — they bind and block instead of binding and signaling (Cody et al., 1995).
Evidence
- Human: No human studies. This is a non-clinical research peptide; there are no registered clinical trials of CHEMBL318020 on ClinicalTrials.gov.
- In vitro: In the Cody et al. (1995) SAR series, this analog was characterized in radioligand-binding assays against endothelin receptor type A (~1000 nM) and endothelin receptor type B (~6000 nM), and in a functional assay measuring inhibition of ET-1-stimulated arachidonic acid release in rabbit renal vascular smooth muscle cells (IC50 ≈ 450 nM, the value reported in this card's subtitle). All three numbers are recorded in the ChEMBL bioactivity record (assay document CHEMBL1128478) and trace back to the same J. Med. Chem. paper.
- Animal: No in vivo data reported for this specific analog; the lead compound of the parent series (PD 142893) was characterized in animal pharmacology, but the 5-mer recorded here was not advanced.
Regulatory status
- US/EU: Not a regulated medicine. Research chemical only; no approval, no IND, no orphan designation.
- WADA: Not on the WADA prohibited list as a named substance.
- ChEMBL classification: Logged as a peptide research compound (CHEMBL318020); no associated drug development programme is publicly recorded.
Related peptides
Other endothelin-receptor-targeting peptides in the broader literature include the parent lead PD 142893 (Ac-DDip-Leu-Asp-Ile-Ile-Trp) and its N-methylated successor PD 156252, both linear hexapeptide ETA/ETB antagonists from the same Parke-Davis series, and the cyclic pentapeptide BQ-123, the prototype ETA-selective antagonist derived from a Streptomyces natural product. None of these are currently on the platform as standalone cards.
▸full evidence table1 metrics
| metric | value | tool |
|---|---|---|
| IC50 | 450 nM | GPCRDB/ChEMBL |
▸structural qualityopenfold3
| metric | value | note |
|---|---|---|
| gpde | 0.779 | global PDE — lower = better |
| disorder | 0.250 | fraction disordered |
| chain pair ipTM (A, B) | 0.871 | 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{pep10322,
sequence = {LDEIW},
target = {ednra},
author = {peptidemodel},
year = {2026},
status = {bioassayed}
}