@bgicli/bgicli 2.1.1 → 2.2.0

package/data/skills/tooluniverse-network-pharmacology/SKILL.md

@@ -0,0 +1,1312 @@
+---
+name: tooluniverse-network-pharmacology
+description: Construct and analyze compound-target-disease networks for drug repurposing, polypharmacology discovery, and systems pharmacology. Builds multi-layer networks from ChEMBL, OpenTargets, STRING, DrugBank, Reactome, FAERS, and 60+ other ToolUniverse tools. Calculates Network Pharmacology Scores (0-100), identifies repurposing candidates, predicts mechanisms, and analyzes polypharmacology. Use when users ask about drug repurposing via network analysis, multi-target drug effects, compound-target-disease networks, systems pharmacology, or polypharmacology.
+---
+
+# Network Pharmacology Pipeline
+
+Construct and analyze compound-target-disease (C-T-D) networks to identify drug repurposing opportunities, understand polypharmacology, and predict drug mechanisms using systems pharmacology approaches.
+
+**IMPORTANT**: Always use English terms in tool calls (drug names, disease names, target names), even if the user writes in another language. Only try original-language terms as a fallback if English returns no results. Respond in the user's language.
+
+---
+
+## When to Use This Skill
+
+Apply when users:
+- Ask "Can [drug] be repurposed for [disease] based on network analysis?"
+- Want to understand multi-target (polypharmacology) effects of a compound
+- Need compound-target-disease network construction and analysis
+- Ask about network proximity between drug targets and disease genes
+- Want systems pharmacology analysis of a drug or target
+- Ask about drug repurposing candidates ranked by network metrics
+- Need mechanism prediction for a drug in a new indication
+- Want to identify hub genes in disease networks as therapeutic targets
+- Ask about disease module coverage by a compound's targets
+
+**NOT for** (use other skills instead):
+- Simple drug repurposing without network analysis -> Use `tooluniverse-drug-repurposing`
+- Single target validation -> Use `tooluniverse-drug-target-validation`
+- Adverse event detection only -> Use `tooluniverse-adverse-event-detection`
+- General disease research -> Use `tooluniverse-disease-research`
+- GWAS interpretation -> Use `tooluniverse-gwas-snp-interpretation`
+
+---
+
+## Input Parameters
+
+| Parameter | Required | Description | Example |
+|-----------|----------|-------------|---------|
+| **entity** | Yes | Compound name/ID, target gene symbol/ID, or disease name/ID | `metformin`, `EGFR`, `Alzheimer disease` |
+| **entity_type** | No | Type hint: `compound`, `target`, or `disease` (auto-detected if omitted) | `compound` |
+| **analysis_mode** | No | `compound-to-disease`, `disease-to-compound`, `target-centric`, `bidirectional` (default) | `bidirectional` |
+| **secondary_entity** | No | Second entity for focused analysis (e.g., disease for compound input) | `Alzheimer disease` |
+
+---
+
+## Network Pharmacology Score (0-100)
+
+### Score Components
+
+**Network Proximity** (0-35 points):
+- Strong proximity (Z < -2, p < 0.01): 35 points
+- Moderate proximity (Z < -1, p < 0.05): 20 points
+- Weak proximity (Z < -0.5): 10 points
+- No proximity: 0 points
+
+**Clinical Evidence** (0-25 points):
+- Approved for related indication: 25 points
+- Active clinical trials: 15 points
+- Completed trials with positive results: 10 points
+- Preclinical only: 5 points
+
+**Target-Disease Association** (0-20 points):
+- Strong genetic evidence (GWAS, rare variants): 20 points
+- Moderate evidence (pathways, literature): 12 points
+- Weak evidence (computational only): 5 points
+
+**Safety Profile** (0-10 points):
+- FDA-approved, favorable safety: 10 points
+- Known manageable adverse events: 7 points
+- Significant safety concerns: 3 points
+- Black box warning relevant to indication: 0 points
+
+**Mechanism Plausibility** (0-10 points):
+- Clear pathway mechanism with functional evidence: 10 points
+- Indirect mechanism via network neighbors: 6 points
+- Purely computational prediction: 2 points
+
+### Priority Tiers
+
+| Score | Tier | Recommendation |
+|-------|------|----------------|
+| **80-100** | Tier 1 | High repurposing potential - proceed with experimental validation |
+| **60-79** | Tier 2 | Good potential - needs mechanistic validation |
+| **40-59** | Tier 3 | Moderate potential - high-risk/high-reward, needs extensive validation |
+| **0-39** | Tier 4 | Low potential - consider alternative approaches |
+
+### Evidence Grading System
+
+| Tier | Symbol | Criteria | Examples |
+|------|--------|----------|----------|
+| **T1** | [T1] | Human clinical proof, regulatory evidence | FDA-approved indication, Phase III trial, patient genomics |
+| **T2** | [T2] | Functional experimental evidence | Bioactivity data (IC50 < 1 uM), CRISPR screen, animal model |
+| **T3** | [T3] | Association/computational evidence | GWAS hit, network proximity, pathway enrichment, expression |
+| **T4** | [T4] | Prediction, annotation, text-mining | AlphaFold prediction, database annotation, literature co-mention |
+
+---
+
+## KEY PRINCIPLES
+
+1. **Report-first approach** - Create report file FIRST, then populate progressively
+2. **Entity disambiguation FIRST** - Resolve all identifiers before analysis
+3. **Bidirectional network** - Construct C-T-D network comprehensively from both directions
+4. **Network metrics** - Calculate proximity, centrality, module overlap quantitatively
+5. **Rank candidates** - Prioritize by composite Network Pharmacology Score
+6. **Mechanism prediction** - Explain HOW drug could work for disease via network paths
+7. **Clinical feasibility** - FDA-approved drugs ranked higher than preclinical
+8. **Safety context** - Flag known adverse events and off-target liabilities
+9. **Evidence grading** - Grade all evidence T1-T4
+10. **Negative results documented** - "No data" is data; empty sections are failures
+11. **Source references** - Every finding must cite the source tool/database
+12. **Completeness checklist** - Mandatory section at end showing analysis coverage
+
+---
+
+## Complete Workflow
+
+### Phase 0: Entity Disambiguation and Report Setup
+
+**Step 0.1**: Create the report file immediately.
+
+```python
+# Create report file FIRST
+report_path = "[entity]_network_pharmacology_report.md"
+# Write header and placeholder sections
+```
+
+**Step 0.2**: Resolve the input entity to all required identifiers.
+
+```python
+from tooluniverse import ToolUniverse
+tu = ToolUniverse(use_cache=True)
+tu.load_tools()
+
+# === COMPOUND DISAMBIGUATION ===
+# Get ChEMBL ID from drug name
+drug_info = tu.tools.OpenTargets_get_drug_chembId_by_generic_name(
+    drugName="metformin"
+)
+# Returns: {data: {search: {hits: [{id: "CHEMBL1431", name: "METFORMIN", ...}]}}}
+chembl_id = drug_info['data']['search']['hits'][0]['id']
+
+# Get drug details (mechanism, indications)
+drug_desc = tu.tools.OpenTargets_get_drug_id_description_by_name(
+    drugName="metformin"
+)
+
+# Get DrugBank info
+drugbank_info = tu.tools.drugbank_get_drug_basic_info_by_drug_name_or_id(
+    query="metformin", case_sensitive=False, exact_match=True, limit=1
+)
+# Returns: {status: "success", data: {drug_name: ..., drugbank_id: ..., ...}}
+
+# Get PubChem CID and SMILES
+pubchem_cid = tu.tools.PubChem_get_CID_by_compound_name(
+    name="metformin"
+)
+# Returns: {IdentifierList: {CID: [4091]}}
+cid = pubchem_cid['IdentifierList']['CID'][0]
+
+# Get SMILES
+pubchem_props = tu.tools.PubChem_get_compound_properties_by_CID(
+    cid=cid
+)
+# Returns: {CID: ..., MolecularWeight: ..., ConnectivitySMILES: ..., IUPACName: ...}
+
+# === TARGET DISAMBIGUATION ===
+# Get Ensembl ID from gene symbol
+target_info = tu.tools.OpenTargets_get_target_id_description_by_name(
+    targetName="PSEN1"
+)
+# Returns: {data: {search: {hits: [{id: "ENSG00000080815", name: "PSEN1", ...}]}}}
+ensembl_id = target_info['data']['search']['hits'][0]['id']
+
+# Get gene details from Ensembl
+gene_details = tu.tools.ensembl_lookup_gene(
+    gene_id=ensembl_id, species='homo_sapiens'
+)
+# Returns: {status: "success", data: {display_name: ..., biotype: ..., ...}}
+
+# Get MyGene info for cross-references
+mygene = tu.tools.MyGene_query_genes(query="PSEN1")
+
+# === DISEASE DISAMBIGUATION ===
+# Get disease ID and description
+disease_info = tu.tools.OpenTargets_get_disease_id_description_by_name(
+    diseaseName="Alzheimer disease"
+)
+# Returns: {data: {search: {hits: [{id: "MONDO_0004975", name: "Alzheimer disease", ...}]}}}
+disease_id = disease_info['data']['search']['hits'][0]['id']
+
+# Get disease description
+disease_desc = tu.tools.OpenTargets_get_disease_description_by_efoId(
+    efoId=disease_id
+)
+
+# Get cross-references
+disease_ids = tu.tools.OpenTargets_get_disease_ids_by_efoId(efoId=disease_id)
+```
+
+---
+
+### Phase 1: Network Node Identification
+
+**Step 1.1**: Identify compound nodes.
+
+```python
+# Get drug targets and mechanism of action from OpenTargets
+drug_moa = tu.tools.OpenTargets_get_drug_mechanisms_of_action_by_chemblId(
+    chemblId=chembl_id
+)
+# Returns: {data: {drug: {mechanismsOfAction: {rows: [{mechanismOfAction: ..., actionType: ..., targetName: ..., targets: [{id, approvedSymbol}]}]}}}}
+
+# Get associated targets from OpenTargets
+drug_targets_ot = tu.tools.OpenTargets_get_associated_targets_by_drug_chemblId(
+    chemblId=chembl_id, size=50
+)
+# Returns: {data: {drug: {linkedTargets: {count: N, rows: [{id, approvedSymbol}]}}}}
+
+# Get targets from DrugBank
+drug_targets_db = tu.tools.drugbank_get_targets_by_drug_name_or_drugbank_id(
+    query="metformin", case_sensitive=False, exact_match=True, limit=1
+)
+# Returns: {status: "success", data: {drug_name: ..., targets: [{id, name, organism, actions}]}}
+
+# Get drug-gene interactions from DGIdb
+dgidb_interactions = tu.tools.DGIdb_get_drug_gene_interactions(
+    genes=["PSEN1", "APP", "BACE1"]  # for disease-to-compound mode
+)
+# Returns: {data: {genes: {nodes: [{name, interactions: [{drug: {name, conceptId}, interactionTypes: [{type}]}]}]}}}
+
+# Get chemical-gene interactions from CTD
+ctd_genes = tu.tools.CTD_get_chemical_gene_interactions(
+    input_terms="Metformin"
+)
+# Returns: {data: [{ChemicalName, GeneSymbol, InteractionActions, ...}]}
+
+# Get STITCH chemical-protein interactions
+stitch_id = tu.tools.STITCH_resolve_identifier(
+    identifier="metformin", species=9606
+)
+# Then query interactions
+stitch_interactions = tu.tools.STITCH_get_chemical_protein_interactions(
+    identifiers=["CIDm000004091"], species=9606
+)
+
+# Get current indications
+drug_indications = tu.tools.OpenTargets_get_drug_indications_by_chemblId(
+    chemblId=chembl_id, size=50
+)
+# Returns: {data: {drug: {indications: {rows: [{disease: {id, name}, maxPhaseForIndication, references}]}}}}
+
+# Check FDA approval status
+fda_approval = tu.tools.OpenTargets_get_drug_approval_status_by_chemblId(
+    chemblId=chembl_id
+)
+
+# Get associated diseases for drug (all trials/investigations)
+drug_diseases = tu.tools.OpenTargets_get_associated_diseases_by_drug_chemblId(
+    chemblId=chembl_id, size=50
+)
+# Returns: {data: {drug: {linkedDiseases: {count: N, rows: [{id, name, description}]}}}}
+```
+
+**Step 1.2**: Identify target nodes (disease-associated targets).
+
+```python
+# Get disease-associated targets from OpenTargets
+disease_targets = tu.tools.OpenTargets_get_associated_targets_by_disease_efoId(
+    efoId=disease_id, limit=50
+)
+# Returns: {data: {disease: {associatedTargets: {count: N, rows: [{target: {id, approvedSymbol}, score}]}}}}
+
+# Get disease-target evidence for top targets
+for target in disease_targets['data']['disease']['associatedTargets']['rows'][:10]:
+    evidence = tu.tools.OpenTargets_target_disease_evidence(
+        efoId=disease_id,
+        ensemblId=target['target']['id']
+    )
+
+# Get GWAS evidence for targets
+gwas_studies = tu.tools.OpenTargets_search_gwas_studies_by_disease(
+    diseaseIds=[disease_id], size=20
+)
+# Returns: {data: {studies: {count: N, rows: [...]}}}
+
+# Get gene-disease associations from CTD
+ctd_diseases = tu.tools.CTD_get_gene_diseases(
+    input_terms="PSEN1"
+)
+
+# Get Pharos target info (druggability levels)
+for gene in ["PSEN1", "APP", "BACE1"]:
+    pharos = tu.tools.Pharos_get_target(target_name=gene)
+    # Returns target development level (Tclin, Tchem, Tbio, Tdark)
+```
+
+**Step 1.3**: Identify disease nodes and related conditions.
+
+```python
+# Get related/similar diseases
+related_diseases = tu.tools.OpenTargets_get_similar_entities_by_disease_efoId(
+    efoId=disease_id, size=10, threshold=0.5
+)
+# Returns: {data: {disease: {similarEntities: [{id, category, score, object: {id, name}}]}}}
+
+# Get disease hierarchy (children/parents)
+disease_children = tu.tools.OpenTargets_get_disease_descendants_children_by_efoId(
+    efoId=disease_id
+)
+disease_parents = tu.tools.OpenTargets_get_disease_ancestors_parents_by_efoId(
+    efoId=disease_id
+)
+
+# Get phenotypes associated with disease
+disease_phenotypes = tu.tools.OpenTargets_get_associated_phenotypes_by_disease_efoId(
+    efoId=disease_id, size=20
+)
+
+# Get therapeutic areas
+disease_areas = tu.tools.OpenTargets_get_disease_therapeutic_areas_by_efoId(
+    efoId=disease_id
+)
+```
+
+---
+
+### Phase 2: Network Edge Construction
+
+**Step 2.1**: Compound-target edges (bioactivity data).
+
+```python
+# Get ChEMBL bioactivity data for drug targets
+chembl_activities = tu.tools.ChEMBL_get_target_activities(
+    target_chembl_id__exact="CHEMBL2111455",  # example target ChEMBL ID
+    limit=50
+)
+# Returns activity data with pchembl_value, standard_type (IC50, Ki, etc.)
+
+# Search ChEMBL mechanisms (all mechanisms for drug)
+all_mechanisms = tu.tools.ChEMBL_search_mechanisms(
+    query="metformin", limit=50
+)
+
+# Get DrugBank drug targets with action types
+db_targets = tu.tools.drugbank_get_targets_by_drug_name_or_drugbank_id(
+    query="metformin", case_sensitive=False, exact_match=True, limit=1
+)
+# Returns: targets with action type (inhibitor, substrate, etc.)
+
+# Get pharmacology from DrugBank
+db_pharmacology = tu.tools.drugbank_get_pharmacology_by_drug_name_or_drugbank_id(
+    query="metformin", case_sensitive=False, exact_match=True, limit=1
+)
+
+# Get BindingDB ligands for key targets (if UniProt ID available)
+# binding_data = tu.tools.BindingDB_get_ligands_by_uniprot(uniprot_accession="P49768")
+```
+
+**Step 2.2**: Target-disease edges (genetic and functional associations).
+
+```python
+# Get OpenTargets target-disease evidence
+for target in top_disease_targets[:10]:
+    td_evidence = tu.tools.OpenTargets_target_disease_evidence(
+        efoId=disease_id,
+        ensemblId=target['target']['id']
+    )
+    # Returns: evidence across datasources (genetics, pathways, literature, etc.)
+
+# Get GWAS associations for key genes
+for gene_symbol in ["PSEN1", "APP", "APOE"]:
+    gwas_assoc = tu.tools.GWAS_search_associations_by_gene(gene_name=gene_symbol)
+
+# Get gene-disease links from CTD
+ctd_gene_diseases = tu.tools.CTD_get_gene_diseases(
+    input_terms="PSEN1"
+)
+
+# Get PharmGKB gene details (pharmacogenomics)
+pharmgkb_gene = tu.tools.PharmGKB_get_gene_details(gene_symbol="PSEN1")
+```
+
+**Step 2.3**: Compound-disease edges (clinical evidence).
+
+```python
+# Get clinical trial evidence
+trials = tu.tools.search_clinical_trials(
+    query_term="metformin",
+    condition="Alzheimer",
+    pageSize=20
+)
+# Returns: {studies: [{NCT ID, brief_title, brief_summary, ...}]}
+
+# Also search with clinical_trials_search
+trials2 = tu.tools.clinical_trials_search(
+    query="metformin Alzheimer disease",
+    limit=20
+)
+
+# Get CTD chemical-disease associations
+ctd_chem_diseases = tu.tools.CTD_get_chemical_diseases(
+    input_terms="Metformin"
+)
+# Returns: [{ChemicalName, DiseaseName, DirectEvidence: "therapeutic"|"marker/mechanism", ...}]
+
+# Literature evidence (PubMed co-mentions)
+pubmed_results = tu.tools.PubMed_search_articles(
+    query="metformin Alzheimer disease",
+    max_results=50
+)
+# Returns: list of {pmid, title, authors, journal, pub_date, ...}
+
+# Europe PMC search for broader coverage
+europepmc_results = tu.tools.EuropePMC_search_articles(
+    query="metformin Alzheimer disease",
+    limit=50
+)
+```
+
+**Step 2.4**: Target-target edges (PPI network).
+
+```python
+# Get STRING protein-protein interactions
+string_ppi = tu.tools.STRING_get_interaction_partners(
+    protein_ids=["PSEN1", "APP", "APOE", "BACE1", "MAPT"],
+    species=9606,
+    limit=20
+)
+# Returns: {status: "success", data: [{stringId_A, stringId_B, preferredName_A, preferredName_B, score, ...}]}
+
+# Get full STRING network
+string_network = tu.tools.STRING_get_network(
+    protein_ids=["PSEN1", "APP", "APOE", "BACE1", "MAPT"],
+    species=9606
+)
+
+# Get IntAct interactions
+intact_results = tu.tools.intact_search_interactions(
+    query="PSEN1", max=20
+)
+
+# Get OpenTargets target interactions
+ot_interactions = tu.tools.OpenTargets_get_target_interactions_by_ensemblID(
+    ensemblId="ENSG00000080815",  # PSEN1
+    size=20
+)
+# Returns: {data: {target: {interactions: {count: N, rows: [{intA, targetA: {id, approvedSymbol}, intB, targetB: {id, approvedSymbol}, score, sourceDatabase}]}}}}
+
+# HumanBase tissue-specific PPI
+humanbase_ppi = tu.tools.humanbase_ppi_analysis(
+    gene_list=["PSEN1", "APP", "APOE", "BACE1", "MAPT"],
+    tissue="brain",
+    max_node=50,
+    interaction="sn",
+    string_mode="physical"
+)
+```
+
+---
+
+### Phase 3: Network Analysis
+
+**Step 3.1**: Network topology analysis (computed from collected data).
+
+```
+Compute from Phase 2 data:
+
+1. Node Degree:
+   - Count connections per node from STRING + IntAct + OpenTargets interactions
+   - Drug targets: connections from bioactivity data
+   - Disease genes: connections from PPI data
+
+2. Hub Identification:
+   - Nodes with degree > mean + 2*SD are hubs
+   - Hub genes in disease module = priority therapeutic targets
+
+3. Betweenness Centrality:
+   - Nodes on shortest paths between drug targets and disease genes
+   - High betweenness = potential mediating/bridging targets
+
+4. Network Modules:
+   - Disease module: cluster of disease-associated genes in PPI
+   - Drug module: cluster of drug target genes in PPI
+   - Module overlap = direct network relevance
+
+5. Shortest Paths:
+   - Paths from each drug target to each disease gene via PPI
+   - Shortest path length < 2 = direct interaction
+   - Path length 2-3 = close proximity
+   - Path length > 4 = distant, weaker association
+```
+
+**Step 3.2**: Network proximity calculation.
+
+```
+Network Proximity Z-score (computed from data):
+
+1. Collect drug target set T_d from Phase 1
+2. Collect disease gene set G_d from Phase 1
+3. For each drug target t in T_d and disease gene g in G_d:
+   - Find shortest path d(t,g) in PPI network from Phase 2
+4. Compute closest proximity: d_c = mean of min distances
+5. Compare against random expectation:
+   - Sample N random gene sets of same size as T_d
+   - Compute proximity for each random set
+   - Z = (d_c - mean_random) / sd_random
+6. Z < -2: strong proximity (35 points)
+   Z < -1: moderate proximity (20 points)
+   Z < -0.5: weak proximity (10 points)
+   Z >= -0.5: no proximity (0 points)
+
+Practical computation from STRING/OpenTargets PPI data:
+- Count direct interactions between drug targets and disease genes
+- Count shared PPI partners (second-degree connections)
+- Calculate overlap coefficient = shared_partners / min(degree_t, degree_d)
+- Use number of shared pathways as additional proximity metric
+```
+
+**Step 3.3**: Functional enrichment analysis.
+
+```python
+# STRING functional enrichment for disease genes
+disease_gene_symbols = [t['target']['approvedSymbol']
+                        for t in disease_targets['data']['disease']['associatedTargets']['rows'][:20]]
+
+string_enrichment = tu.tools.STRING_functional_enrichment(
+    protein_ids=disease_gene_symbols,
+    species=9606
+)
+
+# STRING PPI enrichment (statistical test for network connectivity)
+string_ppi_enrich = tu.tools.STRING_ppi_enrichment(
+    protein_ids=disease_gene_symbols,
+    species=9606
+)
+
+# Enrichr pathway analysis
+enrichr_results = tu.tools.enrichr_gene_enrichment_analysis(
+    gene_list=disease_gene_symbols,
+    libs=["KEGG_2021_Human", "Reactome_2022", "GO_Biological_Process_2023"]
+)
+# Returns enrichment results per library
+
+# Reactome pathway enrichment
+reactome_enrichment = tu.tools.ReactomeAnalysis_pathway_enrichment(
+    identifiers=" ".join(disease_gene_symbols)
+)
+# Returns: {data: {pathways: [{pathway_id, name, p_value, fdr, entities_found, ...}]}}
+```
+
+---
+
+### Phase 4: Drug Repurposing Predictions
+
+**Step 4.1**: Identify and rank repurposing candidates.
+
+```python
+# For disease-to-compound mode: Find drugs targeting disease genes
+repurposing_candidates = []
+
+for target in disease_targets['data']['disease']['associatedTargets']['rows'][:20]:
+    gene_symbol = target['target']['approvedSymbol']
+    ensembl_id = target['target']['id']
+    target_score = target['score']
+
+    # Get drugs from OpenTargets
+    target_drugs = tu.tools.OpenTargets_get_associated_drugs_by_target_ensemblID(
+        ensemblId=ensembl_id, size=20
+    )
+
+    # Get drugs from DGIdb
+    dgidb_drugs = tu.tools.DGIdb_get_drug_gene_interactions(genes=[gene_symbol])
+
+    # Get drugs from DrugBank
+    drugbank_drugs = tu.tools.drugbank_get_drug_name_and_description_by_target_name(
+        query=gene_symbol, case_sensitive=False, exact_match=False, limit=20
+    )
+
+    # Collect and deduplicate candidates
+    # Score each by: target_disease_score * drug_target_affinity * approval_status
+
+# For compound-to-disease mode: Already have drug targets, find their diseases
+for target in drug_targets:
+    # Get diseases associated with each drug target
+    target_diseases = tu.tools.OpenTargets_get_diseases_phenotypes_by_target_ensembl(
+        ensemblId=target['id'], size=20
+    )
+```
+
+**Step 4.2**: Mechanism prediction for repurposing candidates.
+
+```python
+# For each repurposing candidate, trace the network path:
+# Drug -> Direct targets -> PPI neighbors -> Disease genes
+
+# Get drug mechanism
+drug_moa = tu.tools.OpenTargets_get_drug_mechanisms_of_action_by_chemblId(
+    chemblId=candidate_chembl_id
+)
+
+# Get pathways shared between drug targets and disease genes
+drug_target_genes = [t['approvedSymbol'] for t in drug_moa_targets]
+combined_genes = list(set(drug_target_genes + disease_gene_symbols[:10]))
+
+# Pathway enrichment for combined gene set
+combined_pathways = tu.tools.ReactomeAnalysis_pathway_enrichment(
+    identifiers=" ".join(combined_genes)
+)
+
+# Check for specific pathway overlap
+drug_pathways = tu.tools.drugbank_get_pathways_reactions_by_drug_or_id(
+    query=drug_name, case_sensitive=False, exact_match=True, limit=1
+)
+```
+
+---
+
+### Phase 5: Polypharmacology Analysis
+
+**Step 5.1**: Multi-target profiling.
+
+```python
+# Get ALL targets of compound (on-targets + off-targets)
+# From OpenTargets
+all_drug_targets = tu.tools.OpenTargets_get_associated_targets_by_drug_chemblId(
+    chemblId=chembl_id, size=100
+)
+
+# From DrugBank (includes enzymes, carriers, transporters)
+db_full_targets = tu.tools.drugbank_get_targets_by_drug_name_or_drugbank_id(
+    query=drug_name, case_sensitive=False, exact_match=True, limit=1
+)
+
+# From CTD (chemical-gene interactions, includes indirect)
+ctd_interactions = tu.tools.CTD_get_chemical_gene_interactions(
+    input_terms=drug_name
+)
+
+# Classify targets: primary (mechanism) vs secondary (off-target)
+# Count disease module coverage
+drug_target_set = set(drug_target_genes)
+disease_gene_set = set(disease_gene_symbols[:50])
+overlap = drug_target_set & disease_gene_set
+coverage = len(overlap) / len(disease_gene_set) if disease_gene_set else 0
+
+# Target family analysis
+for gene in drug_target_genes[:10]:
+    target_class = tu.tools.OpenTargets_get_target_classes_by_ensemblID(
+        ensemblId=gene_ensembl_id
+    )
+```
+
+**Step 5.2**: Selectivity analysis.
+
+```python
+# Get target druggability and development levels
+for gene in drug_target_genes[:10]:
+    # DGIdb druggability
+    druggability = tu.tools.DGIdb_get_gene_druggability(genes=[gene])
+
+    # Pharos target development level
+    pharos_info = tu.tools.Pharos_get_target(target_name=gene)
+    # Tclin = known drug targets, Tchem = has chemical tools, Tbio = has biology, Tdark = dark target
+
+    # OpenTargets tractability
+    tractability = tu.tools.OpenTargets_get_target_tractability_by_ensemblID(
+        ensemblId=gene_ensembl_id
+    )
+```
+
+---
+
+### Phase 6: Safety and Toxicity Context
+
+**Step 6.1**: Adverse event profiling.
+
+```python
+# Get FAERS adverse event data
+faers_ae = tu.tools.FAERS_search_reports_by_drug_and_reaction(
+    drug_name=drug_name, limit=100
+)
+
+# Get serious events
+faers_serious = tu.tools.FAERS_filter_serious_events(
+    operation="filter_serious_events",
+    drug_name=drug_name,
+    seriousness_type="all"
+)
+
+# Get death reports
+faers_death = tu.tools.FAERS_count_death_related_by_drug(
+    medicinalproduct=drug_name
+)
+# Returns: [{term: "alive", count: N}, {term: "death", count: N}]
+
+# Calculate disproportionality for key AEs
+faers_signal = tu.tools.FAERS_calculate_disproportionality(
+    operation="calculate_disproportionality",
+    drug_name=drug_name,
+    adverse_event="lactic acidosis"  # example
+)
+# Returns: {metrics: {PRR: {value, ci_95_lower, ci_95_upper}, ROR: {...}}, signal_detection: {signal_detected, signal_strength}}
+
+# Get FDA warnings
+fda_warnings = tu.tools.FDA_get_warnings_and_cautions_by_drug_name(
+    drug_name=drug_name
+)
+
+# Get black box warning status
+bbox_warning = tu.tools.OpenTargets_get_drug_blackbox_status_by_chembl_ID(
+    chemblId=chembl_id
+)
+
+# Get drug adverse events from OpenTargets
+ot_ae = tu.tools.OpenTargets_get_drug_adverse_events_by_chemblId(
+    chemblId=chembl_id
+)
+# Returns: {data: {drug: {adverseEvents: {count, rows: [{name, meddraCode, count, logLR}]}}}}
+
+# Get drug warnings from OpenTargets
+drug_warnings = tu.tools.OpenTargets_get_drug_warnings_by_chemblId(
+    chemblId=chembl_id
+)
+```
+
+**Step 6.2**: Target safety profiling.
+
+```python
+# For each drug target, assess safety
+for target_ensembl_id in drug_target_ensembl_ids[:10]:
+    # OpenTargets target safety profile
+    safety = tu.tools.OpenTargets_get_target_safety_profile_by_ensemblID(
+        ensemblId=target_ensembl_id
+    )
+
+    # Gene constraint (is target essential?)
+    constraints = tu.tools.gnomad_get_gene_constraints(gene_symbol=gene_symbol)
+    # High pLI (>0.9) = loss-of-function intolerant = essential gene = safety concern
+
+    # Expression pattern (broadly expressed = more off-target risk)
+    expression = tu.tools.HPA_get_rna_expression_by_source(
+        gene_name=gene_symbol,
+        source_type="tissue",
+        source_name="brain"
+    )
+```
+
+---
+
+### Phase 7: Validation Evidence
+
+**Step 7.1**: Clinical precedent.
+
+```python
+# Search clinical trials for drug + disease combination
+trials = tu.tools.search_clinical_trials(
+    query_term=drug_name,
+    condition=disease_name,
+    pageSize=20
+)
+
+# Get trial details for each match
+for trial in trials.get('studies', [])[:5]:
+    nct_id = trial['NCT ID']
+    trial_details = tu.tools.clinical_trials_get_details(nct_id=nct_id)
+    trial_outcomes = tu.tools.extract_clinical_trial_outcomes(nct_id=nct_id)
+    trial_ae = tu.tools.extract_clinical_trial_adverse_events(nct_id=nct_id)
+
+# Check approved indications
+approved = tu.tools.OpenTargets_get_approved_indications_by_drug_chemblId(
+    chemblId=chembl_id
+)
+# Returns: {data: {drug: {approvedIndications: ["EFO_XXXXX", ...]}}}
+```
+
+**Step 7.2**: Literature evidence.
+
+```python
+# PubMed search for drug-disease co-mentions
+pubmed_evidence = tu.tools.PubMed_search_articles(
+    query=f"{drug_name} {disease_name} repurposing OR repositioning OR network pharmacology",
+    max_results=50
+)
+# Returns: list of {pmid, title, authors, journal, pub_date, ...}
+
+# Europe PMC with broader scope
+europepmc_evidence = tu.tools.EuropePMC_search_articles(
+    query=f"{drug_name} {disease_name}",
+    limit=50
+)
+
+# OpenTargets publications for drug
+ot_drug_pubs = tu.tools.OpenTargets_get_publications_by_drug_chemblId(
+    chemblId=chembl_id, size=20
+)
+
+# OpenTargets publications for disease
+ot_disease_pubs = tu.tools.OpenTargets_get_publications_by_disease_efoId(
+    efoId=disease_id, size=20
+)
+
+# Get guideline searches
+guidelines = tu.tools.PubMed_Guidelines_Search(query=f"{drug_name} {disease_name}")
+```
+
+**Step 7.3**: Experimental evidence.
+
+```python
+# ChEMBL bioactivity data
+chembl_bioactivity = tu.tools.ChEMBL_search_drugs(
+    query=drug_name, limit=10
+)
+
+# Check ADMET predictions (for novel formulation contexts)
+if smiles:
+    admet = tu.tools.ADMETAI_predict_toxicity(smiles=[smiles])
+    bbb = tu.tools.ADMETAI_predict_BBB_penetrance(smiles=[smiles])
+    bioavail = tu.tools.ADMETAI_predict_bioavailability(smiles=[smiles])
+
+# PharmGKB pharmacogenomics data
+pharmgkb_drug = tu.tools.PharmGKB_get_drug_details(drug_name=drug_name)
+pharmgkb_clin = tu.tools.PharmGKB_get_clinical_annotations(query=drug_name)
+```
+
+---
+
+### Phase 8: Report Generation
+
+**Step 8.1**: Compute Network Pharmacology Score.
+
+```
+Score Calculation:
+
+1. Network Proximity Score (0-35):
+   - Count direct drug target <-> disease gene interactions in PPI
+   - Count shared PPI partners
+   - Count shared pathways
+   - Map to Z-score equivalent based on overlap significance
+
+2. Clinical Evidence Score (0-25):
+   - Search clinical trials for drug-disease pair
+   - Check approved indications for related diseases
+   - Check max clinical trial phase
+
+3. Target-Disease Association Score (0-20):
+   - Average OpenTargets association score for drug targets in disease
+   - Weight by evidence type (genetic > functional > computational)
+
+4. Safety Score (0-10):
+   - FDA approval status (+5)
+   - Black box warning (-3)
+   - Death reports proportion
+   - Off-target count penalty
+
+5. Mechanism Plausibility Score (0-10):
+   - Known mechanism for related indication (+5)
+   - Pathway evidence (+3)
+   - Network path length to disease module (+2)
+
+Total: sum of components (0-100)
+```
+
+**Step 8.2**: Generate comprehensive report.
+
+```markdown
+# Network Pharmacology Analysis: [Entity]
+
+## Executive Summary
+[2-3 sentence summary of key findings]
+
+## Network Pharmacology Score: [X]/100 - [Tier]
+| Component | Score | Max | Evidence |
+|-----------|-------|-----|----------|
+| Network Proximity | X | 35 | [summary] |
+| Clinical Evidence | X | 25 | [summary] |
+| Target-Disease Association | X | 20 | [summary] |
+| Safety Profile | X | 10 | [summary] |
+| Mechanism Plausibility | X | 10 | [summary] |
+| **TOTAL** | **X** | **100** | |
+
+## 1. Entity Profile
+### Compound: [Name]
+- ChEMBL ID: [ID]
+- DrugBank ID: [ID]
+- SMILES: [SMILES]
+- Mechanism: [MOA]
+- Approval status: [status]
+- Current indications: [list]
+
+### Disease: [Name]
+- MONDO/EFO ID: [ID]
+- Description: [brief]
+- Top associated targets: [list with scores]
+- Related diseases: [list]
+
+## 2. Network Topology Summary
+- **Total nodes**: X (Y compounds, Z targets, W diseases)
+- **Total edges**: X (Y C-T, Z T-D, W C-D, V T-T)
+- **Network density**: X
+- **Hub nodes**: [list of top hub genes]
+- **Modules detected**: X
+
+### Drug Target Module
+[List drug targets with degree and betweenness]
+
+### Disease Gene Module
+[List disease genes with degree and betweenness]
+
+### Module Overlap
+[Shared genes, shared pathways, overlap coefficient]
+
+## 3. Network Proximity
+- **Proximity measure**: [metric used]
+- **Z-score**: [value]
+- **Direct interactions**: X drug target-disease gene pairs
+- **Shared PPI partners**: X genes
+- **Shared pathways**: X pathways
+- **Interpretation**: [strong/moderate/weak proximity]
+
+## 4. Top Repurposing Candidates (Ranked)
+
+### Candidate 1: [Drug Name] - Score: X/100
+**ChEMBL ID**: [ID] | **Status**: [Approved/Clinical/Preclinical]
+**Current indications**: [list]
+**Network path**: Drug -> [target1, target2] -> [PPI] -> [disease gene1, gene2]
+**Mechanism prediction**: [how drug could work for disease]
+**Clinical evidence**: [trials, literature]
+**Safety**: [key concerns]
+**Evidence grade**: [T1-T4]
+
+[Repeat for top 10 candidates]
+
+## 5. Polypharmacology Profile
+### Target Coverage
+- Total drug targets: X
+- Disease module targets hit: Y (Z%)
+- Primary targets: [list with actions]
+- Off-targets: [list with potential effects]
+
+### Multi-Target Effects
+[Analysis of synergistic vs antagonistic target modulation]
+
+### Disease Module Coverage
+[How well drug targets cover the disease network]
+
+## 6. Pathway Analysis
+### Drug-Affected Pathways
+[Ranked list of pathways affected by drug]
+
+### Disease-Associated Pathways
+[Ranked list of pathways associated with disease]
+
+### Overlapping Pathways (Mechanism)
+[Pathways shared between drug and disease - these explain the mechanism]
+
+## 7. Safety Considerations
+### Adverse Events
+[Top AEs with PRR/ROR where available]
+
+### Target Safety Flags
+[Targets with known safety liabilities]
+
+### Off-Target Risks
+[Off-targets in critical tissues]
+
+### Drug-Drug Interaction Context
+[Key DDI considerations]
+
+## 8. Clinical Precedent
+### Clinical Trials
+[List of relevant trials with NCT IDs and status]
+
+### Literature Evidence
+[Key publications supporting or refuting repurposing hypothesis]
+- N papers found for [drug] + [disease]
+- Key findings: [summary]
+
+### Pharmacogenomics
+[Relevant PGx data]
+
+## 9. Evidence Summary Table
+| Finding | Source | Evidence Grade | Confidence |
+|---------|--------|---------------|------------|
+| [finding1] | [tool/database] | [T1-T4] | [High/Medium/Low] |
+| ... | ... | ... | ... |
+
+## 10. Recommendations
+### Immediate Actions
+1. [Action 1 - e.g., review clinical trial NCT00620191]
+2. [Action 2 - e.g., validate mechanism in cell model]
+
+### Further Investigation
+1. [Investigation 1]
+2. [Investigation 2]
+
+### Risk Mitigation
+1. [Risk 1 and mitigation strategy]
+
+## Completeness Checklist
+| Phase | Status | Tools Used | Key Findings |
+|-------|--------|------------|--------------|
+| Entity Disambiguation | Done/Partial/Failed | [tools] | [summary] |
+| Compound Node ID | Done/Partial/Failed | [tools] | [summary] |
+| Target Node ID | Done/Partial/Failed | [tools] | [summary] |
+| Disease Node ID | Done/Partial/Failed | [tools] | [summary] |
+| C-T Edges | Done/Partial/Failed | [tools] | [summary] |
+| T-D Edges | Done/Partial/Failed | [tools] | [summary] |
+| C-D Edges | Done/Partial/Failed | [tools] | [summary] |
+| T-T Edges (PPI) | Done/Partial/Failed | [tools] | [summary] |
+| Network Topology | Done/Partial/Failed | [computed] | [summary] |
+| Network Proximity | Done/Partial/Failed | [computed] | [summary] |
+| Pathway Enrichment | Done/Partial/Failed | [tools] | [summary] |
+| Repurposing Candidates | Done/Partial/Failed | [tools] | [summary] |
+| Mechanism Prediction | Done/Partial/Failed | [analysis] | [summary] |
+| Polypharmacology | Done/Partial/Failed | [tools] | [summary] |
+| Safety/Toxicity | Done/Partial/Failed | [tools] | [summary] |
+| Clinical Precedent | Done/Partial/Failed | [tools] | [summary] |
+| Literature Evidence | Done/Partial/Failed | [tools] | [summary] |
+| Report Generation | Done/Partial/Failed | - | [summary] |
+```
+
+---
+
+## Tool Parameter Reference (Verified)
+
+### Compound Identification
+| Tool | Key Parameters | Response Structure |
+|------|---------------|-------------------|
+| `OpenTargets_get_drug_chembId_by_generic_name` | `drugName: str` | `{data: {search: {hits: [{id, name, description}]}}}` |
+| `OpenTargets_get_drug_id_description_by_name` | `drugName: str` | `{data: {search: {hits: [{id, name, description}]}}}` |
+| `drugbank_get_drug_basic_info_by_drug_name_or_id` | `query: str`, `case_sensitive: bool`, `exact_match: bool`, `limit: int` (ALL required) | `{status, data: {drug_name, drugbank_id, ...}}` |
+| `PubChem_get_CID_by_compound_name` | `name: str` | `{IdentifierList: {CID: [int]}}` |
+| `PubChem_get_compound_properties_by_CID` | `cid: int` | `{CID, MolecularWeight, ConnectivitySMILES, IUPACName}` |
+| `ChEMBL_search_drugs` | `query: str`, `limit: int` | `{status, data: {drugs: [...]}}` |
+
+### Target Identification
+| Tool | Key Parameters | Response Structure |
+|------|---------------|-------------------|
+| `OpenTargets_get_target_id_description_by_name` | `targetName: str` | `{data: {search: {hits: [{id, name, description}]}}}` |
+| `ensembl_lookup_gene` | `gene_id: str`, `species: str` (REQUIRED, e.g., "homo_sapiens") | `{status, data: {display_name, biotype, ...}}` |
+| `MyGene_query_genes` | `query: str` | Gene info with cross-references |
+| `Pharos_get_target` | `target_name: str` | Target with development level |
+
+### Disease Identification
+| Tool | Key Parameters | Response Structure |
+|------|---------------|-------------------|
+| `OpenTargets_get_disease_id_description_by_name` | `diseaseName: str` | `{data: {search: {hits: [{id, name, description}]}}}` |
+| `OpenTargets_get_disease_description_by_efoId` | `efoId: str` | `{data: {disease: {id, name, description}}}` |
+| `OpenTargets_get_disease_ids_by_efoId` | `efoId: str` | Disease cross-references |
+
+### Network Edges
+| Tool | Key Parameters | Response Structure |
+|------|---------------|-------------------|
+| `STRING_get_interaction_partners` | `protein_ids: list[str]`, `species: int` (9606), `limit: int` | `{status, data: [{stringId_A, stringId_B, preferredName_A, preferredName_B, score}]}` |
+| `STRING_get_network` | `protein_ids: list[str]`, `species: int` | Network data |
+| `STRING_functional_enrichment` | `protein_ids: list[str]`, `species: int` | Enrichment results |
+| `STRING_ppi_enrichment` | `protein_ids: list[str]`, `species: int` | PPI enrichment statistics |
+| `OpenTargets_get_target_interactions_by_ensemblID` | `ensemblId: str`, `size: int` | `{data: {target: {interactions: {count, rows: [{intA, targetA, intB, targetB, score}]}}}}` |
+| `intact_search_interactions` | `query: str`, `max: int` | Interaction data |
+| `humanbase_ppi_analysis` | `gene_list: list`, `tissue: str`, `max_node: int`, `interaction: str`, `string_mode: str` (ALL required) | Tissue-specific PPI |
+
+### Drug-Target Edges
+| Tool | Key Parameters | Response Structure |
+|------|---------------|-------------------|
+| `OpenTargets_get_drug_mechanisms_of_action_by_chemblId` | `chemblId: str` | `{data: {drug: {mechanismsOfAction: {rows: [{mechanismOfAction, actionType, targets}]}}}}` |
+| `OpenTargets_get_associated_targets_by_drug_chemblId` | `chemblId: str`, `size: int` | `{data: {drug: {linkedTargets: {count, rows}}}}` |
+| `drugbank_get_targets_by_drug_name_or_drugbank_id` | `query, case_sensitive, exact_match, limit` (ALL required) | `{status, data: {targets: [{id, name, organism, actions}]}}` |
+| `DGIdb_get_drug_gene_interactions` | `genes: list[str]` | `{data: {genes: {nodes: [{name, interactions}]}}}` |
+| `CTD_get_chemical_gene_interactions` | `input_terms: str` | `{data: [{ChemicalName, GeneSymbol, InteractionActions}]}` |
+| `ChEMBL_get_target_activities` | `target_chembl_id__exact: str` | Activity data with pchembl_value |
+
+### Target-Disease Edges
+| Tool | Key Parameters | Response Structure |
+|------|---------------|-------------------|
+| `OpenTargets_get_associated_targets_by_disease_efoId` | `efoId: str`, `limit: int` | `{data: {disease: {associatedTargets: {count, rows: [{target: {id, approvedSymbol}, score}]}}}}` |
+| `OpenTargets_target_disease_evidence` | `efoId: str`, `ensemblId: str` (BOTH required) | Evidence data across datasources |
+| `CTD_get_gene_diseases` | `input_terms: str` | `{data: [{GeneName, DiseaseName, DirectEvidence}]}` |
+| `GWAS_search_associations_by_gene` | `gene_name: str` | GWAS association data |
+
+### Drug-Disease Edges
+| Tool | Key Parameters | Response Structure |
+|------|---------------|-------------------|
+| `OpenTargets_get_drug_indications_by_chemblId` | `chemblId: str`, `size: int` | `{data: {drug: {indications: {rows: [{disease, maxPhaseForIndication}]}}}}` |
+| `OpenTargets_get_associated_diseases_by_drug_chemblId` | `chemblId: str`, `size: int` | `{data: {drug: {linkedDiseases: {count, rows}}}}` |
+| `CTD_get_chemical_diseases` | `input_terms: str` | `{data: [{ChemicalName, DiseaseName, DirectEvidence}]}` |
+| `search_clinical_trials` | `query_term: str` (REQUIRED), `condition: str`, `pageSize: int` | `{studies: [{NCT ID, brief_title, ...}]}` |
+
+### Pathway Analysis
+| Tool | Key Parameters | Response Structure |
+|------|---------------|-------------------|
+| `ReactomeAnalysis_pathway_enrichment` | `identifiers: str` (space-separated, NOT array) | `{data: {pathways: [{pathway_id, name, p_value, fdr, entities_found}]}}` |
+| `enrichr_gene_enrichment_analysis` | `gene_list: list[str]`, `libs: list[str]` (REQUIRED) | Enrichment per library |
+| `drugbank_get_pathways_reactions_by_drug_or_id` | `query, case_sensitive, exact_match, limit` | Pathway data |
+
+### Safety Tools
+| Tool | Key Parameters | Response Structure |
+|------|---------------|-------------------|
+| `FAERS_calculate_disproportionality` | `operation: str`, `drug_name: str`, `adverse_event: str` | `{metrics: {PRR, ROR, IC}, signal_detection}` |
+| `FAERS_filter_serious_events` | `operation: str`, `drug_name: str`, `seriousness_type: str` | Serious event data |
+| `FAERS_count_death_related_by_drug` | `medicinalproduct: str` | `[{term, count}]` |
+| `OpenTargets_get_drug_adverse_events_by_chemblId` | `chemblId: str` | `{data: {drug: {adverseEvents: {count, rows}}}}` |
+| `OpenTargets_get_drug_warnings_by_chemblId` | `chemblId: str` | Drug warning data |
+| `OpenTargets_get_target_safety_profile_by_ensemblID` | `ensemblId: str` | Target safety data |
+| `gnomad_get_gene_constraints` | `gene_symbol: str` | Gene constraint (pLI, LOEUF) |
+| `FDA_get_warnings_and_cautions_by_drug_name` | `drug_name: str` | FDA warning text |
+
+### Literature Tools
+| Tool | Key Parameters | Response Structure |
+|------|---------------|-------------------|
+| `PubMed_search_articles` | `query: str`, `max_results: int` | list of `{pmid, title, authors, journal, pub_date}` |
+| `EuropePMC_search_articles` | `query: str`, `limit: int` | Article list |
+| `OpenTargets_get_publications_by_drug_chemblId` | `chemblId: str`, `size: int` | Publication data |
+
+---
+
+## Response Format Notes
+
+**DrugBank tools**: ALL require `query`, `case_sensitive`, `exact_match`, `limit` (4 params, ALL required).
+
+**FAERS analytics tools** (disproportionality, compare, filter, stratify, rollup, trends): ALL require `operation` parameter.
+
+**FAERS count tools** (count_death, count_reactions, etc.): Use `medicinalproduct` NOT `drug_name`.
+
+**OpenTargets tools**: Return nested `{data: {entity: {field: ...}}}` structure.
+
+**PubMed_search_articles**: Returns plain **list** of dicts, NOT `{articles: [...]}`.
+
+**PubChem CID lookup**: Returns `{IdentifierList: {CID: [...]}}` (NO data wrapper).
+
+**ReactomeAnalysis_pathway_enrichment**: Takes space-separated `identifiers` string, NOT array.
+
+**ensembl_lookup_gene**: REQUIRES `species='homo_sapiens'` parameter.
+
+**STRING tools**: Return `{status: "success", data: [...]}`.
+
+**CTD tools**: Return `{data: [...]}` with potentially large result sets.
+
+---
+
+## Fallback Strategies
+
+| Phase | Primary Tool | Fallback 1 | Fallback 2 |
+|-------|-------------|-----------|-----------|
+| Compound ID | OpenTargets drug lookup | ChEMBL search | PubChem CID lookup |
+| Target ID | OpenTargets target lookup | ensembl_lookup_gene | MyGene_query_genes |
+| Disease ID | OpenTargets disease lookup | ols_search_efo_terms | CTD_get_chemical_diseases |
+| Drug targets | OpenTargets drug mechanisms | DrugBank targets | DGIdb interactions |
+| Disease targets | OpenTargets disease targets | CTD gene-diseases | GWAS associations |
+| PPI network | STRING interactions | OpenTargets interactions | IntAct interactions |
+| Pathways | ReactomeAnalysis enrichment | enrichr enrichment | STRING functional enrichment |
+| Clinical trials | search_clinical_trials | clinical_trials_search | PubMed clinical |
+| Safety | FAERS + FDA | OpenTargets AEs | DrugBank safety |
+| Literature | PubMed search | EuropePMC search | OpenTargets publications |
+
+---
+
+## Common Use Patterns
+
+### Pattern 1: Drug Repurposing via Network Proximity
+```
+Input: compound (metformin) + disease (Alzheimer disease)
+Mode: compound-to-disease
+
+Flow:
+1. Resolve metformin -> CHEMBL1431, DB00331, CID:4091
+2. Get metformin targets (OpenTargets, DrugBank, DGIdb)
+3. Get Alzheimer disease genes (OpenTargets, GWAS)
+4. Build PPI network (STRING, OpenTargets interactions)
+5. Calculate proximity between drug targets and disease genes
+6. Score and rank by Network Pharmacology Score
+7. Predict mechanism via shared pathways
+8. Validate with clinical trials and literature
+```
+
+### Pattern 2: Disease-Driven Drug Discovery
+```
+Input: disease (lupus)
+Mode: disease-to-compound
+
+Flow:
+1. Resolve lupus -> MONDO/EFO ID
+2. Get disease-associated targets (top 50)
+3. For each target, find approved drugs (OpenTargets, DGIdb, DrugBank)
+4. Build C-T-D network from all drug-target-disease edges
+5. Rank drugs by: number of disease targets hit, network proximity, safety
+6. Identify polypharmacology advantages (drugs hitting multiple disease targets)
+```
+
+### Pattern 3: Target-Centric Network
+```
+Input: target (EGFR)
+Mode: target-centric
+
+Flow:
+1. Resolve EGFR -> ENSG00000146648
+2. Get all compounds targeting EGFR (with bioactivity)
+3. Get all diseases associated with EGFR
+4. Build PPI network around EGFR
+5. Identify which compounds could bridge to which diseases
+6. Rank compound-disease pairs by network metrics
+```
+
+### Pattern 4: Polypharmacology Profiling
+```
+Input: compound (aspirin)
+Mode: bidirectional
+
+Flow:
+1. Resolve aspirin -> CHEMBL25
+2. Get ALL targets (not just primary)
+3. Map targets to disease modules
+4. Identify multi-target coverage across diseases
+5. Analyze synergistic vs antagonistic effects
+6. Compare selectivity across target families
+```
+
+### Pattern 5: Mechanism Elucidation
+```
+Input: compound (rapamycin) + disease (aging/longevity)
+Mode: compound-to-disease
+
+Flow:
+1. Resolve rapamycin -> CHEMBL413 (sirolimus)
+2. Get mechanism: mTOR inhibitor
+3. Map mTOR pathway to aging-related genes
+4. Trace network paths: rapamycin -> mTOR -> autophagy -> aging genes
+5. Assess pathway overlap and functional enrichment
+6. Provide mechanistic explanation
+```
+
+---
+
+## Edge Cases
+
+### Promiscuous Compounds (many targets)
+- Limit initial target retrieval to top 50 by confidence
+- Classify into primary (mechanism) vs secondary (off-target)
+- Focus network analysis on primary targets first
+- Note polypharmacology implications
+
+### Orphan Diseases (limited data)
+- Expand to parent disease categories in ontology
+- Use related diseases from OpenTargets similar entities
+- Leverage pathway-level analysis over gene-level
+- Note data limitations in report
+
+### Novel Targets (no known drugs)
+- Focus on target biology and disease association
+- Use DGIdb druggability assessment
+- Search for chemical probes (OpenTargets chemical probes)
+- Suggest target-based screening approaches
+
+### Large Networks (>100 nodes)
+- Prioritize top-scored edges
+- Use network modules rather than full network
+- Focus on shortest paths between entities
+- Summarize statistics rather than listing all nodes
+
+### Disconnected Networks
+- Report disconnection explicitly
+- Analyze drug module and disease module separately
+- Look for pathway-level connections as bridge
+- Note that disconnection suggests low repurposing potential
+
+---
+
+## Troubleshooting
+
+**"Disease not found"**:
+- Try disease synonyms (e.g., "Alzheimer's disease" vs "Alzheimer disease")
+- Use EFO/MONDO ID directly if known
+- Search with `OpenTargets_multi_entity_search_by_query_string(queryString=...)` for broader matching
+- Try parent disease category
+
+**"No drugs found for target"**:
+- Target may be Tdark (no chemical tools) - check with Pharos
+- Expand to target family or pathway
+- Search DGIdb which aggregates multiple sources
+- Check chemical probes as starting points
+
+**"No PPI data"**:
+- Try different protein identifiers (gene symbol, UniProt, Ensembl protein)
+- Use multiple PPI databases (STRING + IntAct + OpenTargets)
+- Lower confidence threshold in STRING
+- Use pathway co-membership as proxy for interaction
+
+**"Network proximity not significant"**:
+- Drug targets may be functionally distant from disease module
+- Try expanding disease gene set (increase limit)
+- Consider indirect mechanisms via shared pathways
+- Report honestly - not all drug-disease pairs have network support
+
+**"DrugBank parameter errors"**:
+- ALL DrugBank tools require 4 params: `query`, `case_sensitive`, `exact_match`, `limit`
+- Use `case_sensitive=False`, `exact_match=True` for exact drug name matching
+- Use `exact_match=False` for broader searches
+
+**"FAERS operation errors"**:
+- Analytics tools (disproportionality, compare, filter, stratify) need `operation` param
+- Count tools use `medicinalproduct` NOT `drug_name`
+- Check FAERS tool name carefully to determine which pattern
+
+---
+
+## Resources
+
+For focused drug repurposing (without network analysis): [tooluniverse-drug-repurposing](../tooluniverse-drug-repurposing/SKILL.md)
+For target validation: [tooluniverse-drug-target-validation](../tooluniverse-drug-target-validation/SKILL.md)
+For adverse event detection: [tooluniverse-adverse-event-detection](../tooluniverse-adverse-event-detection/SKILL.md)
+For systems biology: [tooluniverse-systems-biology](../tooluniverse-systems-biology/SKILL.md)
+For protein interactions: [tooluniverse-protein-interactions](../tooluniverse-protein-interactions/SKILL.md)