tooluniverse-peptide-target-deorphanization

• SKILL.mdcore · 17,871 bytes
• SKILL.mdcore · 17,871 bytes
• SKILL.mdcore · 17,871 bytes
• SKILL.mdcore · 17,871 bytes
• SKILL.mdcore · 17,871 bytes
• SKILL.mdcore · 17,871 bytes
• references/phases.mddoc · 42,878 bytes
• scripts/cofold_screen.pyruns · 10,486 bytes
• scripts/deorphanize_peptide.pyruns · 44,152 bytes

# Peptide Target Deorphanization

Deorphanize a peptide: given a peptide **sequence** plus an **observed phenotype** (and often a *hypothesized* target the peptide does NOT actually bind), find its likely real protein target(s) — using ToolUniverse's keyless characterization, homology, target-family, phenotype, cross-species, and (optional, key-gated) co-folding tools.

**The target can be anything, not just a GPCR.** A *target-class router* (GPCR ligand / ion-channel toxin / protease target / cytokine or growth-factor receptor / integrin ligand / antimicrobial / unknown) classifies the peptide up front and adapts the enumeration strategy. GPCRs are the best-trodden case (and the validated control), but the pipeline's spine — homology, motif, phenotype, cross-species, co-fold — is target-class-agnostic, and family enumeration uses **HGNC gene-family (general) + InterPro (general) + GPCRdb (GPCR-only cross-check)**.

## Core reasoning: LOOK UP, DON'T GUESS

The failure mode this skill defends against is **guessing a target from the peptide's name or its assumed mechanism**. A peptide can be **phenotypically active yet not bind the hypothesized target** — because it hits a *paralog*, a *different family member*, or the *same receptor in a different species* whose binding interface has diverged. So:

1. **Never assert a target from memory.** Every candidate must come from a tool result (homology hit, family enumeration, phenotype association, or structural co-fold), with the tool name and accession recorded.
2. **Anchor on PHENOTYPE × STRUCTURE/SEQUENCE plausibility, not on the peptide's reputed mechanism.** The real target is the intersection of (a) what the *sequence/motif/structure* says it could bind and (b) what the *phenotype* says is biologically relevant. A name-level guess ("it's a GLP-1 analog so it's GLP1R") is exactly what produces off-target errors.
3. **Reconcile across species.** "Binds in species A but not B" is usually **interface sequence divergence**, not a different target. Always pull the ortholog set and align the candidate receptor's ligand-binding interface across the assay species before concluding the peptide "doesn't work."
4. **A non-binding result against the hypothesized target is a clue, not a dead end.** It promotes the *paralogs* and *phenotype-shared* receptors to the top of the candidate list.