tooluniverse-target-research

name

tooluniverse-target-research

description

Gather comprehensive biological target intelligence from 9 parallel research paths covering protein info, structure, interactions, pathways, expression, variants, drug interactions, and literature. Features collision-aware searches, evidence grading (T1-T4), explicit Open Targets coverage, and mandatory completeness auditing. Use when users ask about drug targets, proteins, genes, or need target validation, druggability assessment, or comprehensive target profiling.

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.

---

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")
|
+- IDENTIFIER RESOLUTION (always first)
|   +- Check if GPCR -> GPCRdb_get_protein
|
+- PATH 0: Open Targets Foundation (ALWAYS FIRST - fills gaps in all other paths)
|
+- 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

---

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)

---

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
PubChem BioAssay	HTS screening hits and dose-response
DepMap	CRISPR essentiality across cancer cell lines
ChEMBL	Bioactivity records and compound counts

See IMPLEMENTATION.md for detailed code and REFERENCE.md for complete tool parameter tables.

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PATH 8: Literature & Research (Collision-Aware)

1. Detect collisions - Check if gene symbol has non-biological meanings
2. Build seed queries - Symbol in title with bio context, full name, UniProt accession
3. Apply collision filter - Add NOT terms for off-topic meanings
4. Expand via citations - For sparse targets (<30 papers), use citation network
5. Classify by evidence tier - T1-T4 based on title/abstract keywords

Tools: PubMed_search_articles, PubMed_get_related, EuropePMC_search_articles, EuropePMC_get_citations, PubTator3_LiteratureSearch, OpenTargets_get_publications_by_target_ensemblID

Populates: Section 11 (Literature & Research Landscape)

See IMPLEMENTATION.md for collision-aware search code.

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Retry Logic & Fallback Chains

Primary Tool	Fallback 1	Fallback 2
ChEMBL_get_target_activities	GtoPdb_get_target_ligands	OpenTargets drugs
intact_get_interactions	STRING_get_protein_interactions	OpenTargets interactions
GO_get_annotations_for_gene	OpenTargets GO	MyGene GO
GTEx_get_median_gene_expression	HPA_get_rna_expression	Document as unavailable
gnomad_get_gene_constraints	OpenTargets constraint	-
DGIdb_get_drug_gene_interactions	OpenTargets drugs	GtoPdb

NEVER silently skip failed tools. Always document failures and fallbacks in the report.

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Completeness Audit (REQUIRED before finalizing)

Run the checklist in EVIDENCE_GRADING.md before finalizing any report:

• Data minimums met for PPIs, expression, diseases, constraints, druggability
• Negative results documented explicitly
• T1-T4 grades in Executive Summary, Disease Associations, Key Papers, Recommendations
• Every data point has source attribution

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Report Template

Create [TARGET]_target_report.md with all 15 sections initialized. See REPORT_FORMAT.md for the full template with section headers, table formats, and completeness checklist.

Initial file structure:

## 1. Executive Summary          ## 9. Druggability & Pharmacology
## 2. Target Identifiers         ## 10. Safety Profile
## 3. Basic Information          ## 11. Literature & Research
## 4. Structural Biology         ## 12. Competitive Landscape
## 5. Function & Pathways        ## 13. Summary & Recommendations
## 6. Protein-Protein Interactions ## 14. Data Sources & Methodology
## 7. Expression Profile         ## 15. Data Gaps & Limitations
## 8. Genetic Variation & Disease

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Quick Reference: Tool Parameters

Tool	Parameter	Notes
Reactome_map_uniprot_to_pathways	id	NOT uniprot_id
ensembl_get_xrefs	id	NOT gene_id
GTEx_get_median_gene_expression	gencode_id, operation	Try versioned ID if empty
OpenTargets_*	ensemblId	camelCase, not ensemblID
STRING_get_protein_interactions	protein_ids, species	List format for IDs
intact_get_interactions	identifier	UniProt accession

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Reference Files

File	Contents
IMPLEMENTATION.md	Detailed code for identifier resolution, GPCR detection, each PATH implementation, retry logic
EVIDENCE_GRADING.md	T1-T4 tier definitions, citation format, completeness audit checklist, data minimums
REPORT_FORMAT.md	Full report template with all 15 sections, table formats, section-specific guidance
REFERENCE.md	Complete tool reference (225+ tools) organized by category with parameters
EXAMPLES.md	Worked examples: EGFR full profile, KRAS druggability, target comparison, CDK4 validation, Alzheimer's targets