tooluniverse-target-research

Comprehensive Target Intelligence Gatherer

Gather complete target intelligence by exploring 9 parallel research paths. Supports targets identified by gene symbol, UniProt accession, Ensembl ID, or gene name.

KEY PRINCIPLES:

1. Report-first approach - Create report file FIRST, then populate progressively
2. Tool parameter verification - Verify params via get_tool_info before calling unfamiliar tools
3. Evidence grading - Grade all claims by evidence strength (T1-T4). See EVIDENCE_GRADING.md
4. Citation requirements - Every fact must have inline source attribution
5. Mandatory completeness - All sections must exist with data minimums or explicit "No data" notes
6. Disambiguation first - Resolve all identifiers before research
7. Negative results documented - "No drugs found" is data; empty sections are failures
8. Collision-aware literature search - Detect and filter naming collisions
9. English-first queries - Always use English terms in tool calls, even if the user writes in another language. Translate gene names, disease names, and search terms to English. Only try original-language terms as a fallback if English returns no results. Respond in the user's language

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When to Use This Skill

Apply when users:

• Ask about a drug target, protein, or gene
• Need target validation or assessment
• Request druggability analysis
• Want comprehensive target profiling
• Ask "what do we know about [target]?"
• Need target-disease associations
• Request safety profile for a target

When NOT to use: Simple protein lookup, drug-only queries, disease-centric queries, sequence retrieval, structure download -- use specialized skills instead.

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Phase 0: Tool Parameter Verification (CRITICAL)

BEFORE calling ANY tool for the first time, verify its parameters:

tool_info = tu.tools.get_tool_info(tool_name="Reactome_map_uniprot_to_pathways")
# Reveals: takes `id` not `uniprot_id`

Known Parameter Corrections

Tool	WRONG Parameter	CORRECT Parameter
Reactome_map_uniprot_to_pathways	uniprot_id	id
ensembl_get_xrefs	gene_id	id
GTEx_get_median_gene_expression	gencode_id only	gencode_id + operation="median"
OpenTargets_*	ensemblID	ensemblId (camelCase)
STRING_get_protein_interactions	single ID	protein_ids (list), species
intact_get_interactions	gene symbol	identifier (UniProt accession)

GTEx Versioned ID Fallback (CRITICAL)

GTEx often requires versioned Ensembl IDs. If ENSG00000123456 returns empty, try ENSG00000123456.{version} from ensembl_lookup_gene.

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Critical Workflow Requirements

1. Report-First Approach (MANDATORY)

DO NOT show the search process or tool outputs to the user. Instead:

1. Create the report file FIRST ([TARGET]_target_report.md) with all section headers and [Researching...] placeholders. See REPORT_FORMAT.md for template.
2. Progressively update each section as data is retrieved.
3. Methodology in appendix only - create separate [TARGET]_methods_appendix.md if requested.

2. Evidence Grading (MANDATORY)

Grade every claim by evidence strength using T1-T4 tiers. See EVIDENCE_GRADING.md for tier definitions, required locations, and citation format.

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Core Strategy: 9 Research Paths

Target Query (e.g., "EGFR" or "P00533")
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+- IDENTIFIER RESOLUTION (always first)
|   +- Check if GPCR -> GPCRdb_get_protein
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+- PATH 0: Open Targets Foundation (ALWAYS FIRST - fills gaps in all other paths)
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+- PATH 1: Core Identity (names, IDs, sequence, organism)
|   +- InterProScan_scan_sequence for novel domain prediction
+- PATH 2: Structure & Domains (3D structure, domains, binding sites)
|   +- If GPCR: GPCRdb_get_structures (active/inactive states)
+- PATH 3: Function & Pathways (GO terms, pathways, biological role)
+- PATH 4: Protein Interactions (PPI network, complexes)
+- PATH 5: Expression Profile (tissue expression, single-cell)
+- PATH 6: Variants & Disease (mutations, clinical significance)
|   +- DisGeNET_search_gene for curated gene-disease associations
+- PATH 7: Drug Interactions (known drugs, druggability, safety)
|   +- Pharos_get_target for TDL classification (Tclin/Tchem/Tbio/Tdark)
|   +- BindingDB_get_ligands_by_uniprot for known ligands
|   +- PubChem_search_assays_by_target_gene for HTS data
|   +- If GPCR: GPCRdb_get_ligands (curated agonists/antagonists)
|   +- DepMap_get_gene_dependencies for target essentiality
+- PATH 8: Literature & Research (publications, trends)

For detailed code implementations of each path, see IMPLEMENTATION.md.

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Identifier Resolution (Phase 1)

Resolve ALL identifiers before any research path. Required IDs:

• UniProt accession (for protein data, structure, interactions)
• Ensembl gene ID + versioned ID (for Open Targets, GTEx)
• Gene symbol (for DGIdb, gnomAD, literature)
• Entrez gene ID (for KEGG, MyGene)
• ChEMBL target ID (for bioactivity)
• Synonyms/full name (for collision-aware literature search)

After resolution, check if target is a GPCR via GPCRdb_get_protein. See IMPLEMENTATION.md for resolution and GPCR detection code.

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PATH 0: Open Targets Foundation (ALWAYS FIRST)

Populates baseline data for Sections 5, 6, 8, 9, 10, 11 before specialized queries.

Endpoint	Report Section	Data Type
OpenTargets_get_diseases_phenotypes_by_target_ensemblId	8	Diseases/phenotypes
OpenTargets_get_target_tractability_by_ensemblId	9	Druggability assessment
OpenTargets_get_target_safety_profile_by_ensemblId	10	Safety liabilities
OpenTargets_get_target_interactions_by_ensemblId	6	PPI network
OpenTargets_get_target_gene_ontology_by_ensemblId	5	GO annotations
OpenTargets_get_publications_by_target_ensemblId	11	Literature
OpenTargets_get_biological_mouse_models_by_ensemblId	8/10	Mouse KO phenotypes
OpenTargets_get_chemical_probes_by_target_ensemblId	9	Chemical probes
OpenTargets_get_associated_drugs_by_target_ensemblId	9	Known drugs

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PATH 1: Core Identity

Tools: UniProt_get_entry_by_accession, UniProt_get_function_by_accession, UniProt_get_recommended_name_by_accession, UniProt_get_alternative_names_by_accession, UniProt_get_subcellular_location_by_accession, MyGene_get_gene_annotation

Populates: Sections 2 (Identifiers), 3 (Basic Information)

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PATH 2: Structure & Domains

Use 3-step structure search chain (do NOT rely solely on PDB text search):

1. UniProt PDB cross-references (most reliable)
2. Sequence-based PDB search (catches missing annotations)
3. Domain-based search (for multi-domain proteins)
4. AlphaFold (always check)

Tools: UniProt_get_entry_by_accession (PDB xrefs), get_protein_metadata_by_pdb_id, PDB_search_similar_structures, alphafold_get_prediction, InterPro_get_protein_domains, UniProt_get_ptm_processing_by_accession

GPCR targets: Also query GPCRdb_get_structures for active/inactive state data.

Populates: Section 4 (Structural Biology)

See IMPLEMENTATION.md for the 3-step chain code.

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PATH 3: Function & Pathways

Tools: GO_get_annotations_for_gene, Reactome_map_uniprot_to_pathways, kegg_get_gene_info, WikiPathways_search, enrichr_gene_enrichment_analysis

Populates: Section 5 (Function & Pathways)

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PATH 4: Protein Interactions

Tools: STRING_get_protein_interactions, intact_get_interactions, intact_get_complex_details, BioGRID_get_interactions, HPA_get_protein_interactions_by_gene

Minimum: 20 interactors OR documented explanation.

Populates: Section 6 (Protein-Protein Interactions)

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PATH 5: Expression Profile

GTEx with versioned ID fallback + HPA as backup. For comprehensive HPA data, also query cell line expression comparison.

Tools: GTEx_get_median_gene_expression, HPA_get_rna_expression_by_source, HPA_get_comprehensive_gene_details_by_ensembl_id, HPA_get_subcellular_location, HPA_get_cancer_prognostics_by_gene, HPA_get_comparative_expression_by_gene_and_cellline, CELLxGENE_get_expression_data

Populates: Section 7 (Expression Profile)

See IMPLEMENTATION.md for GTEx fallback and HPA extended expression code.

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PATH 6: Variants & Disease

Separate SNVs from CNVs in ClinVar results. Integrate DisGeNET for curated gene-disease association scores.

Tools: gnomad_get_gene_constraints, clinvar_search_variants, OpenTargets_get_diseases_phenotypes_by_target_ensembl, DisGeNET_search_gene, civic_get_variants_by_gene, cBioPortal_get_mutations

Required: All 4 constraint scores (pLI, LOEUF, missense Z, pRec).

Populates: Section 8 (Genetic Variation & Disease)

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PATH 7: Druggability & Target Validation

Comprehensive druggability assessment including TDL classification, binding data, screening data, and essentiality.

Tools: OpenTargets_get_target_tractability_by_ensemblID, DGIdb_get_gene_druggability, DGIdb_get_drug_gene_interactions, ChEMBL_search_targets, ChEMBL_get_target_activities, Pharos_get_target, BindingDB_get_ligands_by_uniprot, PubChem_search_assays_by_target_gene, DepMap_get_gene_dependencies, OpenTargets_get_target_safety_profile_by_ensemblID, OpenTargets_get_biological_mouse_models_by_ensemblID

GPCR targets: Also query GPCRdb_get_ligands.

Populates: Sections 9 (Druggability), 10 (Safety), 12 (Competitive Landscape)

Key Data Sources for Druggability

Source	What It Provides
Pharos TDL	Tclin/Tchem/Tbio/Tdark classification
BindingDB	Experimental Ki/IC50/Kd values
Pub

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