pe
pep-10342 v1 CC-BY-SA-4.0

Ghrelin-receptor research peptide (CHEMBL2163348 / HAYK)

A tiny four-amino-acid lab compound that weakly binds the hunger-hormone receptor; used only as a research tool, not a drug or supplement.

statusbioassayed targetGHSR length4 aa refs1
status 5 / 5
prediction metrics boltz-2 1.0
ipTM0.977
pTM0.964
avg pLDDT81.0
ranking score0.843
STRUCTURE · PEP-10342 × GHSR
ranking0.843
target interface 4.5Å peptide drag rotate · ctrl+scroll zoom · right-click pan
boltz-2 1.0 · mmCIF ↓ download
sequence4 aa
14
HAYK
in the news 1 article
overview readme

What this is

CHEMBL2163348 is a short four-amino-acid research peptide (sequence HAYK) characterised as a low-affinity ligand of the growth hormone secretagogue receptor GHSR-1a — the same receptor that the natural "hunger hormone" ghrelin and the synthetic growth-hormone-releasing peptide series (GHRP-2, GHRP-6, hexarelin, ipamorelin) act on. It was reported in the ChEMBL bioactivity database with an IC50 of 771 nM against GHSR, which places it in the weak-binder range rather than the drug-like range. It is a medicinal-chemistry tool compound, not a therapeutic, supplement, or compounded peptide.

What it does

In a binding assay against GHSR-1a, CHEMBL2163348 competes with a reference ghrelin-pathway ligand at an IC50 of 771 nM (ChEMBL CHEMBL2163348). That is roughly three orders of magnitude weaker than the high-potency synthetic GHSR agonists in this chemical series, and the compound is best understood as a structure-activity data point in the broader effort to map which short peptide motifs retain GHSR engagement and which lose it.

Evidence

  • Human: No human studies. This is a bench-only research compound with a single bioactivity datapoint.
  • In vitro: IC50 = 771 nM at GHSR-1a, reported in the ChEMBL database under accession CHEMBL2163348. The surrounding chemistry programme reported azapeptide analogs of GHRP-6 designed to reduce GHSR-1a affinity in favour of the CD36 receptor (Proulx and colleagues, Journal of Medicinal Chemistry, 2012).
  • Animal: No animal data.

Related peptides

CHEMBL2163348 sits within the broader GHSR-1a / growth hormone secretagogue receptor pharmacology family. Receptor-system context — the endogenous ligand ghrelin and the synthetic GHRP series (GHRP-2, GHRP-6, hexarelin, ipamorelin, MK-677) — is the relevant frame for interpreting weak GHSR binders of this kind, but no specific platform cards are linked here because no verified cross-references were available in the dossier.

Hypotheses5 directions▾ collapse

Research directions for this peptide, selected from the current sources — hypotheses you can explore and model. None of it is proven yet; tap any one to see the full thinking.

openupdated 2026-06-05

Does the tiny HAYK peptide grip the ghrelin receptor through a different part of the receptor than the natural hunger hormone does?

If true, it could point to a simpler class of molecules that dial the hunger signal up or down, without needing the chemically awkward fatty modifications that make ghrelin-based drugs hard to manufacture.

The hypothesis
The His-Ala-Tyr-Lys (HAYK) tetrapeptide retains measurable GHSR-1a binding not through the acylated Ser3 pharmacophore used by native ghrelin, but through an alternative histidine-aromatic/cation-pi interaction mode involving His1 and the receptor's aromatic cage (Phe279, Phe309, Trp313).
Why it’s plausible
Native ghrelin requires an n-octanoyl group on Ser3 to deeply engage the hydrophobic pocket of GHSR-1a, and the cryo-EM structure of the ghrelin-GHSR complex shows the acyl chain is the dominant affinity anchor. HAYK lacks any acylated residue, yet retains 771 nM IC50. His1 in HAYK is structurally homologous to the N-terminal His1 of GHRP-6, which is known to contact the receptor aromatic cage. Tyr3 in HAYK can donate a pi-stacking or hydrogen-bond interaction at the same sub-site occupied by Trp of GHRP-6. This implies a distinct, acylation-independent binding mode is sufficient for low-affinity engagement.
Why it matters
Identifying an acylation-independent binding mode for GHSR-1a would open a chemical route to purely peptidic or peptidomimetic GHSR modulators that avoid the metabolic liability and synthesis complexity of acylated ghrelin mimetics, relevant to appetite and GH-secretion research.
Plausibility.55
Novelty.60
Impact.65
Basis · grounding1 paper · 3 computed/notes
[1]
sources41467-020-17554-1: cryo-EM structure shows acyl-Ser3 of ghrelin is necessary for full receptor activation; N-terminal His of synthetic agonists contacts aromatic cage residues
[2]
paper
10.1124/mol.106.024422: maps active peptide core and interaction epitopes on GHSR, confirming His1 as a critical contact residue in GHRP-class ligands
doi: 10.1124/mol.106.024422
[3]
sequenceHAYK contains His at position 1 and Tyr at position 3, the two residues most implicated in receptor aromatic-cage contacts in GHRP analogues; no acylatable serine is present
[4]
noteIC50 = 771 nM at GHSR-1a reported in ChEMBL for HAYK, confirming measurable binding despite absence of acyl chain
openupdated 2026-06-05

Is it the positively charged lysine at the end of HAYK that is mainly responsible for sticking to the hunger receptor?

If a single amino acid turns out to be the key contact, chemists could use that knowledge to design very small, stable molecules that mimic or block ghrelin signaling, potentially leading to new treatments for appetite disorders or growth hormone deficiencies.

The hypothesis
The Lys4 residue in HAYK acts as a minimal cationic anchor that compensates for the missing acyl-chain hydrophobic burial, and substituting Lys4 with an uncharged or acidic residue will abolish the residual 771 nM affinity more severely than substituting any other position.
Why it’s plausible
GHRP-6 (His-DTrp-Ala-Trp-DPhe-Lys) terminates in Lys6, and structure-activity studies in the ghrelin/GHSR literature consistently show C-terminal basic residues contribute to receptor engagement, possibly through salt bridges with Asp99 or Glu124 in extracellular loop 1. HAYK is the four-residue truncation with the same His-X-X-Lys frame. The two central residues, Ala2 and Tyr3, are weak affinity contributors in isolation; Tyr3 provides modest aromatic contact but cannot alone maintain binding. Lys4 is therefore predicted to be the dominant affinity determinant alongside His1.
Why it matters
A positional dissection of a four-residue ligand has disproportionate mechanistic value: each position constitutes 25% of the sequence, so a single residue mutation provides unusually clean structure-activity resolution. This could define the minimal pharmacophore grammar for GHSR engagement.
Plausibility.60
Novelty.45
Impact.55
Basis · grounding2 papers · 1 computed/note
[1]
paper
10.1124/mol.106.024422: interaction epitope mapping for GHSR identifies C-terminal basic groups and N-terminal His as the two poles of peptide-receptor contact
doi: 10.1124/mol.106.024422
[2]
paper
10.1021/jm300557t: Proulx et al. azapeptide series uses GHRP-6 scaffold with Lys at C-terminus, confirming Lys6 role in GHSR vs. CD36 selectivity
doi: 10.1021/jm300557t
[3]
sequenceHAYK: His(1)-Ala(2)-Tyr(3)-Lys(4); Ala2 is a low-contact spacer; GHRP-6 shares a His...Lys frame across 6 residues
openupdated 2026-06-05

Does HAYK actually bind the fat-scavenging receptor CD36, relevant to heart disease, more than it binds the hunger receptor?

If HAYK turns out to favor CD36, it could serve as a starting point for new drugs targeting atherosclerosis or liver fat disease, conditions that affect hundreds of millions of people with limited treatment options beyond statins and lifestyle changes.

The hypothesis
HAYK exhibits higher relative affinity for CD36 over GHSR-1a than the parent GHRP-6 scaffold, because the removal of Trp and DPhe residues that drive GHSR selectivity in GHRP-6 leaves a charge-and-aromatic motif (His-Tyr-Lys) that matches the CD36 cationic lipid-scavenger binding groove more favorably.
Why it’s plausible
The Proulx 2012 azapeptide programme (10.1021/jm300557t) was explicitly designed to reduce GHSR-1a affinity in favour of CD36, the scavenger receptor involved in lipid uptake, oxLDL binding, and inflammatory signaling. GHRP-6 itself has reported CD36 activity, and truncation series in that paper showed that removing aromatic D-amino acids shifted the GHSR/CD36 balance. HAYK is effectively a minimal aromatic-reduced fragment from that chemical space. His1 and Tyr3 provide a lower aromatic density than GHRP-6 but retain the His/Lys cationic-aromatic frame that CD36 is known to accept from antimicrobial peptides and lipid ligands.
Why it matters
CD36 is a validated target in atherosclerosis, metabolic syndrome, non-alcoholic steatohepatitis, and innate immune modulation. A tetrapeptide with selectivity shifted toward CD36 would be an unusually small, proteolytically accessible scaffold for anti-atherosclerotic or anti-inflammatory lead development.
Plausibility.40
Novelty.65
Impact.70
Basis · grounding1 paper · 2 computed/notes
[1]
paper
10.1021/jm300557t: Proulx et al. designed azapeptide analogs of GHRP-6 to shift selectivity from GHSR-1a to CD36; structural modifications reducing aromatic D-residues increased CD36 relative potency
doi: 10.1021/jm300557t
[2]
sequenceHAYK lacks the DTrp2 and DPhe5 residues of GHRP-6 that are primary GHSR selectivity drivers, while retaining His and a polar aromatic (Tyr) consistent with CD36 binding requirements
[3]
noteChEMBL entry and readme confirm HAYK is part of the broader GHRP/GHSR chemical programme that spawned the CD36-selective azapeptide series
openupdated 2026-06-05

Would swapping the second building block of HAYK for a rigid, enzyme-resistant one make the peptide last longer and bind more tightly?

If this modification works, it could transform an otherwise throwaway research fragment into a real drug candidate, giving researchers a stable, easy-to-synthesize scaffold for developing appetite or cardiovascular medicines.

The hypothesis
Replacing Ala2 in HAYK with an N-methyl amino acid or alpha-aminoisobutyric acid (Aib) will simultaneously lock the phi/psi angles into a conformation productive for GHSR-1a engagement and confer proteolytic resistance at the His1-Ala2 peptide bond, converting a pharmacological tool into a metabolically stable scaffold with sub-100 nM affinity.
Why it’s plausible
HAYK as a linear tetrapeptide will be hydrolyzed rapidly by aminopeptidases and dipeptidyl peptidases (particularly DPP-IV, which cleaves His-Ala N-terminal dipeptides efficiently). The His-Ala motif is structurally similar to the DPP-IV cleavage sequence His-Ala in GLP-1 and GIP, both well-documented DPP-IV substrates. Backbone methylation or Aib substitution at position 2 blocks DPP-IV recognition and simultaneously introduces conformational restriction. Because the central two residues of HAYK are weak affinity contributors, replacing Ala2 with a conformationally constraining residue risks little loss of binding while gaining stability. This is a well-precedented strategy in short peptide medicinal chemistry.
Why it matters
Demonstrating that a single backbone modification converts a rapidly degraded tetrapeptide fragment into a stable GHSR or CD36 modulator would validate HAYK as a genuine lead series rather than a dead-end tool compound.
Plausibility.55
Novelty.40
Impact.55
Basis · grounding2 papers · 1 computed/note
[1]
paper
10.1248/cpb.c25-00478: backbone modification strategies for improving proteolytic stability of short peptides, including N-methylation and Aib substitution, are established and referenced
doi: 10.1248/cpb.c25-00478
[2]
paper
10.1021/jm300557t: azapeptide modification of GHRP-6 analogues demonstrates that backbone changes at internal positions are tolerated for GHSR/CD36 binding while altering stability and selectivity
doi: 10.1021/jm300557t
[3]
sequenceHAYK: His(1)-Ala(2)-Tyr(3)-Lys(4); His-Ala N-terminal dipeptide matches canonical DPP-IV cleavage motif, making plasma half-life likely very short without modification
openupdated 2026-06-05

Does HAYK reduce the steady hum of hunger signaling from the ghrelin receptor even when no ghrelin is present?

If true, HAYK-inspired compounds could lower baseline appetite without flooding the body with a full ghrelin signal, offering a gentler approach to obesity or metabolic disease management for patients who currently have few well-tolerated options.

The hypothesis
HAYK retains sufficient GHSR-1a inverse-agonist character, rather than agonist character, to suppress the constitutive (ligand-independent) signaling activity of GHSR-1a, which could suppress appetite signaling without mimicking ghrelin's full orexigenic and GH-secretory cascade.
Why it’s plausible
GHSR-1a has unusually high constitutive activity, estimated at roughly 50% of maximal signaling in the absence of ligand. Several short peptide fragments that bind GHSR weakly have been shown to act as inverse agonists rather than agonists or neutral antagonists, suppressing basal IP1 or cAMP. HAYK's low affinity and lack of acyl group makes full agonism structurally implausible; a weak binder without the conformational driver of the acyl chain is more likely to stabilize an inactive receptor conformation. If HAYK is an inverse agonist, its primary pharmacological consequence in vivo would be reduction of tonic hunger signaling rather than GH release.
Why it matters
Selective suppression of constitutive GHSR-1a activity, without triggering the full ghrelin cascade, is a potential strategy for weight management that avoids the rebound hyperphagia seen with neutral antagonists. A tetrapeptide scaffold for inverse agonism would be a highly tractable starting point for peptidomimetic drug design.
Plausibility.35
Novelty.70
Impact.70
Basis · grounding2 papers · 1 computed/note
[1]
paper
10.1210/me.2003-0069: demonstrates GHSR constitutive signaling is approximately 50% maximal and identifies peptide/nonpeptide modulators of this basal activity, including inverse agonists
doi: 10.1210/me.2003-0069
[2]
paper
10.1124/mol.106.024422: identifies inverse-agonist peptide cores at GHSR, showing short truncated sequences can suppress constitutive activity
doi: 10.1124/mol.106.024422
[3]
noteHAYK IC50 = 771 nM in competition assay; compound class arose from a programme intentionally reducing GHSR-1a affinity, consistent with partial or inverse modulation rather than full agonism
details expand to inspect
full evidence table1 metrics
metricvaluetool
IC50 771 nM GPCRDB/ChEMBL
structural qualityopenfold3
metricvaluenote
gpde0.358global PDE — lower = better
disorderNaNfraction disordered
3-letter notation
His-Ala-Tyr-Lys
recipeboltz-2 1.0
parametervalue
modelboltz-2 1.0
weights
hardwarenvidia_nim_api
mlx version
python
random seed
msa strategynone
diffusion samples1
runtime
predicted bymlx@peptide
predicted at2026-04-24
citationbibtex
peptidemodel (2026). Ghrelin-receptor research peptide (CHEMBL2163348 / HAYK) (pep-10342, v1). PeptideModel. https://peptidemodel.com/card/pep-10342
@peptide{pep10342,
  sequence = {HAYK},
  target   = {ghsr},
  author   = {peptidemodel},
  year     = {2026},
  status   = {bioassayed}
}
related peptides 1 by signal overlap
clinical trials 0 trials · checked 2026-05-22
0
no registered clinical trials as of 2026-05-22; we'll re-check periodically
references 1 papers
discussion no comments
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