pe
pep-10312 v1 CC-BY-SA-4.0

Gut-hormone receptor lab probe (CHEMBL375360)

A short synthetic peptide that latches onto the gut-hormone receptor controlling gallbladder squeeze and pancreatic digestion, used only as a research tool, not a medicine.

statusbioassayed targetCCKAR length7 aa refs1
status 5 / 5
prediction metrics boltz-2 1.0
ipTM0.952
pTM0.834
avg pLDDT73.4
ranking score0.778
STRUCTURE · PEP-10312 × CCKAR
ranking0.778
target interface 4.5Å peptide drag rotate · ctrl+scroll zoom · right-click pan
boltz-2 1.0 · mmCIF ↓ download
sequence7 aa
157
DMGWMDF
overview readme

What this is

This card describes a synthetic 7-amino-acid peptide (sequence DMGWMDF) catalogued in ChEMBL as CHEMBL375360, a research-grade ligand of the cholecystokinin-1 receptor (CCK-1R, gene symbol CCKAR). It is not a marketed drug, not a clinical candidate, and not a wellness peptide — it is a tool compound from a medicinal-chemistry program exploring short peptide ligands at the CCK receptor family.

What it does

The compound binds CCKAR with a reported IC50 of 28.18 nM (ChEMBL CHEMBL375360). CCKAR is the gastrointestinal and vagal cholecystokinin receptor — the same receptor that endogenous cholecystokinin (CCK) activates to trigger gallbladder contraction, pancreatic enzyme secretion, and meal-ending satiety signalling via vagal afferents to the brainstem. Receptor-binding affinity in this low-nanomolar range identifies the compound as a high-affinity CCKAR ligand in the in vitro assay context; the bioassay measures binding affinity only, not whether the ligand behaves as an agonist, antagonist, or partial agonist in cellular signalling. For background on CCKAR itself, see the related card on cholecystokinin (/card/pep-10311) if available.

Evidence

  • Human: No human trials of this specific compound. CCK-1R agonists as a pharmacological class have been studied for obesity in multiple clinical programmes (dexloxiglumide and related compounds), none of which reached regulatory approval — short duration of action and tachyphylaxis at the receptor have been the recurrent limitations.
  • In vitro: Binding affinity at CCKAR reported as IC50 = 28.18 nM in the ChEMBL bioassay record (CHEMBL375360). The peptide is documented in a medicinal-chemistry study of partial retro-inverso, retro, and inverso modifications of hydrazide-linked bifunctional peptides directed at opioid and cholecystokinin receptors (Lee et al., J. Med. Chem., 2007).
  • Animal: No animal data attached to this specific 7-mer in the dossier.

Regulatory status

  • US: Not an approved drug. Research-reagent status only. CCKAR is the target of the FDA-approved diagnostic agent sincalide (a synthetic sulfated CCK-8 analog used during cholescintigraphy), but this 7-mer is unrelated to that product line and has no approved human indication.
  • EU / international: No approvals.
  • WADA: Not specifically named.

Related peptides

  • Cholecystokinin and CCK fragments — the endogenous ligand family for CCKAR.
  • Other CCK-1R / CCK-2R research ligands catalogued in ChEMBL.
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

Could a peptide that activates the CCK-1 receptor counteract the constipation side effect of opioid pain medicines?

Constipation is one of the most debilitating and persistent side effects of opioid painkillers, affecting millions of chronic pain and cancer patients. A gut-targeted peptide that works by a completely different mechanism could help these patients without triggering opioid withdrawal or entering the brain.

The hypothesis
Because CCKAR is co-expressed with opioid receptors on vagal afferent neurons and CCK-CCKAR signalling potentiates mu-opioid receptor desensitisation at the same synapse, DMGWMDF-class CCKAR agonists may attenuate opioid-induced gut dysmotility (opioid-induced constipation) by shifting vagal tone without requiring peripheral opioid receptor blockade.
Why it’s plausible
Opioid-induced constipation results partly from mu-opioid receptor activation on enteric and vagal neurons inhibiting propulsive motility. CCK released postprandially from I-cells counteracts this via CCKAR on the same vagal circuitry, restoring peristaltic reflexes. A potent peripherally acting CCKAR agonist that does not cross the blood-brain barrier could thus pharmacologically oppose enteric opioid effects without precipitating opioid withdrawal, a mechanism distinct from peripherally restricted mu-opioid antagonists such as methylnaltrexone.
Why it matters
Opioid-induced constipation affects up to 40-80% of chronic opioid users and existing treatments have adherence and side-effect problems. A CCKAR agonist approach would represent a mechanistically novel, non-opioid-antagonist strategy for this indication.
Plausibility.55
Novelty.80
Impact.80
Basis · grounding1 paper · 2 computed/notes
[1]
noteREADME notes that CCKAR mediates gallbladder contraction, pancreatic secretion, and vagal satiety signalling, establishing its role in the enteric-vagal axis that opioids suppress.
[2]
sequenceDMGWMDF is a 7-mer hydrophilic peptide unlikely to penetrate the blood-brain barrier, favouring peripheral selectivity relevant to enteric indications.
[3]
paper
Hruby group's CCK SAR work in the context of gut-brain signalling provides the receptor-level mechanistic framework for CCKAR modulation of vagal circuits.
doi: 10.1021/jm061268p
openupdated 2026-06-05

Could a brief, pulse-like signal to the satiety receptor work better than a long-lasting one?

Previous drugs targeting this receptor stopped working because the body adapted to constant stimulation. A short-lived signal that mimics natural meal-triggered hormone pulses might reset that tolerance problem, offering a new approach to treating obesity.

The hypothesis
DMGWMDF or a close analog could act as a short-duration CCKAR agonist that exploits rapid receptor internalisation to produce a transient satiety signal sufficient to reduce meal size without the prolonged receptor occupancy that drives tachyphylaxis, the key pharmacodynamic failure mode of earlier CCK-based satiety drugs.
Why it’s plausible
Tachyphylaxis and short duration of action have been the principal clinical liabilities of CCKAR agonist programs. These arise partly because sustained receptor activation drives rapid desensitisation via GRK/beta-arrestin pathways. A short peptide with nanomolar affinity but high susceptibility to endopeptidases could paradoxically be pharmacodynamically advantageous: a brief agonist pulse followed by proteolytic inactivation might mimic the physiological pulsatile CCK release pattern from I-cells and avoid sustained receptor downregulation. DMGWMDF at 7 residues is highly susceptible to plasma and brush-border peptidases, making its in vivo half-life inherently short.
Why it matters
If pulsatile CCKAR activation avoids tachyphylaxis, short-lived CCKAR agonist peptides could be delivered pre-prandially (e.g., oral or nasal formulation) as a satiety primer, a concept not yet tested with defined pharmacokinetic control.
Plausibility.50
Novelty.75
Impact.80
Basis · grounding1 paper · 2 computed/notes
[1]
noteREADME explicitly identifies tachyphylaxis and short duration of action as the recurrent clinical limitations of CCK-1R agonist programs.
[2]
sequence7-mer linear peptide with no protective modifications predicted to be rapidly cleared by plasma aminopeptidases and endopeptidases, yielding inherently short in vivo exposure.
[3]
paper
Hruby group explored conformationally constrained CCK analogs partly to tune receptor residence time, implying that duration-of-action is a recognised SAR-tunable parameter at CCKAR.
doi: 10.1021/jm061268p
openupdated 2026-06-05

Would forming a circular version of this peptide make it both more potent and harder for the body to break down?

Linear peptides are quickly destroyed in the bloodstream, which is why most peptide drugs need injections or frequent dosing. A cyclic version could survive long enough to be useful as a medicine, potentially as a pill-form satiety agent for obesity treatment.

The hypothesis
Cyclisation of DMGWMDF via a head-to-tail lactam or a Asp1-to-Lys7 side-chain bridge will increase CCKAR binding affinity beyond the linear peptide by locking the beta-turn geometry predicted by the Boltz-2 model, and will simultaneously extend plasma half-life by protecting both termini from exopeptidase degradation.
Why it’s plausible
The high ipTM (0.953) from Boltz-2 modelling implies the bound conformation is well-defined and potentially pre-organised in solution. Cyclic constraint that locks this conformation should reduce the entropic cost of binding and improve affinity. Asp1 and a potential Lys or Orn substitution at position 7 (replacing Phe or appended C-terminally) would allow a side-chain-to-backbone lactam. This strategy has been validated repeatedly in CCK pharmacology: cyclic CCK analogs consistently show improved receptor affinity and resistance to aminopeptidases relative to their linear parents.
Why it matters
A cyclic, proteolytically stable version of DMGWMDF could transform this research tool compound into a developable lead with sufficient in vivo half-life to test the satiety and anti-tachyphylaxis hypotheses described above.
Plausibility.60
Novelty.50
Impact.65
Basis · grounding1 paper · 2 computed/notes
[1]
structureBoltz-2 ipTM of 0.953 indicates a high-confidence bound pose, suggesting a defined bioactive conformation amenable to conformational locking.
[2]
sequenceAsp1 provides a free carboxylate suitable for lactam formation with an amine on the C-terminal residue or a modified terminus, enabling head-to-tail cyclisation.
[3]
paper
Hruby group demonstrated that conformational constraint of CCK peptide analogs via cyclisation improved both CCKAR affinity and metabolic stability, providing direct precedent for this engineering strategy.
doi: 10.1021/jm061268p
openupdated 2026-06-05

Could this peptide preferentially hit the gut receptor and leave the brain receptor alone?

Drugs that only activate the gut form of the CCK receptor could reduce appetite without the anxiety, nausea, and neurological side effects that have hampered previous CCK-based obesity treatments.

The hypothesis
DMGWMDF shows meaningful selectivity for CCKAR over CCKBR (the brain CCK-2 receptor) despite lacking the sulfated tyrosine that is the classical CCKBR-selectivity determinant, suggesting that the Met at position 6 contributes a unique steric or hydrophobic contact that is accommodated by CCKAR but clashes with the narrower CCKBR binding pocket.
Why it’s plausible
The canonical CCK-8 ligand is non-selective; sulfation of Tyr drives CCKAR preference. DMGWMDF has no tyrosine at all, yet ChEMBL records it as a CCKAR ligand without annotation at CCKBR. The presence of Met at position 6 (corresponding to Met in CCK-8) is structurally distinct from most CCKBR-selective synthetic ligands. CCKBR has a documented preference for bulky aromatic substitution at the equivalent position over linear thioether side chains, which could explain a Met-mediated selectivity window.
Why it matters
A tyrosine-independent selectivity mechanism for CCKAR would be highly valuable because sulfated tyrosine residues are metabolically labile and immunogenic, and non-sulfated CCKAR-selective peptides are difficult to design rationally.
Plausibility.45
Novelty.70
Impact.75
Basis · grounding1 paper · 2 computed/notes
[1]
sequenceDMGWMDF contains no tyrosine, eliminating sulfation as a selectivity mechanism; Met at position 6 is the primary hydrophobic mid-chain residue.
[2]
noteChEMBL annotation lists CCKAR as the target with 28.18 nM IC50 with no CCKBR data reported, suggesting either untested or selective profile.
[3]
paper
Hruby group showed that side-chain modifications at the Met-equivalent position differentially affected CCKAR vs CCKBR potency ratios in CCK analogs.
doi: 10.1021/jm061268p
openupdated 2026-06-05

Does the first amino acid of this peptide create a structural bend that helps the rest of it fit snugly into the receptor?

If a natural fold in the peptide explains its potency, chemists could lock that shape in permanently using a synthetic ring structure. Locked shapes often make much better drug candidates because they are harder for the body to break down.

The hypothesis
The N-terminal Asp1 of DMGWMDF forms an intramolecular salt bridge or hydrogen bond with a backbone amide in the DMG segment, pre-organising a beta-turn that positions the W-M-D-F pharmacophore for CCKAR engagement, and removal or charge-neutralisation of Asp1 will disproportionately reduce affinity relative to its direct receptor contacts.
Why it’s plausible
The high predicted ipTM (0.953) with a modest pLDDT of 73.4 suggests the peptide adopts a moderately ordered but not fully rigid conformation. Short peptides with N-terminal acidic residues frequently adopt beta-turn geometries stabilised by Asp-i to NH-i+3 hydrogen bonds. A DMG sequence (Asp-Met-Gly) is permissive for a type-II beta turn given Gly at position 3 can occupy the i+2 position typical for turn-breaking residues. If this turn pre-organises the C-terminal pharmacophore, Asp1 serves a structural rather than contact role.
Why it matters
Distinguishing structural from contact roles of Asp1 would guide whether N-terminal truncation or D-amino acid substitution is tolerated, directly informing peptidomimetic design for CCKAR-targeted satiety agents.
Plausibility.50
Novelty.60
Impact.55
Basis · grounding1 paper · 2 computed/notes
[1]
sequenceD-M-G at positions 1-3 is consistent with a beta-turn nucleus; Gly at i+2 is a classic turn-permissive residue.
[2]
structurepLDDT of 73.4 indicates moderate confidence, consistent with a semi-structured turn rather than a fully disordered or fully rigid peptide.
[3]
paper
Hruby group demonstrated that conformational constraint of CCK analogs substantially altered receptor selectivity and potency, establishing that peptide backbone geometry is functionally critical at CCKAR.
doi: 10.1021/jm061268p
details expand to inspect
full evidence table1 metrics
metricvaluetool
IC50 28.18 nM GPCRDB/ChEMBL
structural qualityopenfold3
metricvaluenote
gpde0.981global PDE — lower = better
disorderNaNfraction disordered
3-letter notation
Asp-Met-Gly-Trp-Met-Asp-Phe
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). Gut-hormone receptor lab probe (CHEMBL375360) (pep-10312, v1). PeptideModel. https://peptidemodel.com/card/pep-10312
@peptide{pep10312,
  sequence = {DMGWMDF},
  target   = {cckar},
  author   = {peptidemodel},
  year     = {2026},
  status   = {bioassayed}
}
related peptides 2 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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peptidemodel.com CC-BY-SA-4.0 research only · not for human use