COMPUTE, DON'T DESCRIBE

A drug hitting multiple targets is either polypharmacology (desired multi-target) or promiscuity (undesired off-target). The distinction depends on whether the additional targets contribute to efficacy or cause toxicity.

Use this framework to guide the analysis:

• Desired polypharmacology: multiple targets all lie within the same disease module or pathway. Example: a kinase inhibitor that hits both EGFR and ERBB2 in the same signaling cascade. Look for pathway co-membership and disease module overlap. This is a network proximity argument.
• Off-target promiscuity: additional targets are in unrelated pathways, especially those associated with known toxicity (hERG for cardiotoxicity, CYP3A4 for drug interactions, COX-1 for GI toxicity). Look for these in the safety phase before claiming benefit.
• Repurposing hypothesis: the drug's known targets have strong genetic/functional evidence for the new disease. Network proximity (Z-score) quantifies this. A Z < -2 with p < 0.01 is meaningful signal; a Z near 0 means the targets are essentially unconnected to the disease module.
• Mechanism ambiguity: if a drug has 10+ known targets, do not treat all as therapeutically relevant. Start with primary mechanism-of-action targets, then ask whether secondary targets add to or subtract from the therapeutic window.

Document this reasoning explicitly in the report before listing candidates.

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

NOT for (use other skills instead):

• Simple drug repurposing without network analysis -> tooluniverse-drug-repurposing
• Single target validation -> tooluniverse-drug-target-validation
• Adverse event detection only -> tooluniverse-adverse-event-detection

Key Principles

1. Report-first approach - Create report file FIRST, then populate progressively
2. Entity disambiguation FIRST - Resolve all identifiers before analysis
3. Reason about polypharmacology type - Desired vs. promiscuous (see above)
4. Bidirectional network - Construct C-T-D network from both directions
5. Rank candidates - Prioritize by composite Network Pharmacology Score
6. Mechanism prediction - Explain HOW drug could work 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

Network Pharmacology Score (0-100)

Five components with explicit reasoning at each step:

• Network Proximity (35 pts): Z < -2, p < 0.01 earns full points. A drug whose targets are in a different network neighborhood from the disease module scores near zero here. Do not claim proximity without computing the Z-score.
• Clinical Evidence (25 pts): Approved for related indication earns full points. Clinical trial evidence earns partial credit. Computational prediction alone earns none.
• Target-Disease Association (20 pts): Strong genetic evidence (GWAS, rare variants) for the drug's primary targets in the new disease.
• Safety Profile (10 pts): FDA-approved, favorable safety in target population.
• Mechanism Plausibility (10 pts): A clear pathway mechanism with functional evidence, not just co-mention in literature.

Priority tiers: 80-100 = high repurposing potential (proceed to experimental validation); 60-79 = good potential (needs mechanistic validation); 40-59 = moderate potential (high-risk/high-reward); 0-39 = low potential.

Evidence grades: T1 = human clinical proof; T2 = functional experimental evidence (IC50 < 1 uM, CRISPR screen); T3 = association/computational (GWAS hit, network proximity); T4 = prediction or text-mining only.

Full scoring details: SCORING_REFERENCE.md

Workflow Overview

Phase 0: Entity Disambiguation and Report Setup

• Create report file immediately
• Resolve entity to all required IDs (ChEMBL, DrugBank, PubChem CID, Ensembl, MONDO/EFO)
• Tools: OpenTargets_get_drug_chembId_by_generic_name, drugbank_get_drug_basic_info_by_drug_name_or_id, PubChem_get_CID_by_compound_name, OpenTargets_get_target_id_description_by_name, OpenTargets_get_disease_id_description_by_name

Phase 1: Network Node Identification

• Compound nodes: Drug targets, mechanism of action, current indications
• Target nodes: Disease-associated genes, GWAS targets, druggability levels
• Disease nodes: Related diseases, hierarchy, phenotypes
• Tools: OpenTargets_get_drug_mechanisms_of_action_by_chemblId, OpenTargets_get_associated_targets_by_drug_chemblId, drugbank_get_targets_by_drug_name_or_drugbank_id, DGIdb_get_drug_gene_interactions, CTD_get_chemical_gene_interactions, OpenTargets_get_associated_targets_by_disease_efoId, Pharos_get_target

Phase 2: Network Edge Construction

• C-T edges: Bioactivity data (ChEMBL, DrugBank, BindingDB)
• T-D edges: Genetic/functional associations (OpenTargets evidence, GWAS, CTD)
• C-D edges: Clinical trials, CTD chemical-disease, literature co-mentions
• T-T edges: PPI network (STRING, IntAct, OpenTargets interactions, HumanBase)
• Tools: ChEMBL_get_target_activities, OpenTargets_target_disease_evidence, GWAS_search_associations_by_gene, search_clinical_trials, CTD_get_chemical_diseases, STRING_get_interaction_partners, STRING_get_network, intact_search_interactions, humanbase_ppi_analysis

Phase 3: Network Analysis

• Hub identification: which targets are most connected in the drug-disease subnetwork
• Shortest paths between drug targets and disease genes: how many hops, through which intermediaries
• Network proximity Z-score: are drug targets closer to disease module than random expectation
• Functional enrichment to identify shared biological processes
• Tools: STRING_functional_enrichment, STRING_ppi_enrichment, enrichr_gene_enrichment_analysis, ReactomeAnalysis_pathway_enrichment

Phase 4: Drug Repurposing Predictions

• Identify drugs targeting disease genes (disease-to-compound mode)
• Find diseases associated with drug targets (compound-to-disease mode)
• Rank candidates by composite Network Pharmacology Score
• Predict mechanisms via shared pathways and network paths
• Tools: OpenTargets_get_associated_drugs_by_target_ensemblID, drugbank_get_drug_name_and_description_by_target_name, drugbank_get_pathways_reactions_by_drug_or_id

Phase 5: Polypharmacology Analysis

• Classify each secondary target as contributing to efficacy or representing off-target risk
• Disease module coverage: what fraction of disease genes are hit directly or within 1 hop
• Target family analysis and selectivity
• Tools: OpenTargets_get_target_classes_by_ensemblID, DGIdb_get_gene_druggability, OpenTargets_get_target_tractability_by_ensemblID

Phase 6: Safety and Toxicity Context

• Adverse event profiling (FAERS disproportionality, OpenTargets AEs)
• Target safety (gene constraints, expression, safety profiles)
• FDA warnings, black box status
• Tools: FAERS_calculate_disproportionality, FAERS_filter_serious_events, FAERS_count_death_related_by_drug, FDA_get_warnings_and_cautions_by_drug_name, OpenTargets_get_drug_adverse_events_by_chemblId, OpenTargets_get_target_safety_profile_by_ensemblID, gnomad_get_gene_constraints

Phase 7: Validation Evidence

• Clinical trials for drug-disease pair
• Literature evidence (PubMed, EuropePMC)
• ADMET predictions if SMILES available
• Pharmacogenomics data
• Tools: search_clinical_trials, get_clinical_trial_descriptions, PubMed_search_articles, EuropePMC_search_articles, ADMETAI_predict_toxicity, PharmGKB_get_drug_details

Phase 8: Report Generation

• Compute Network Pharmacology Score from components
• Document polypharmacology reasoning (desired vs. promiscuous)
• Generate report using template
• Include completeness checklist

Full step-by-step code examples: ANALYSIS_PROCEDURES.md Report template: REPORT_TEMPLATE.md

Critical Tool Parameter Notes

• DrugBank tools: ALL require query, case_sensitive, exact_match, limit (4 params, ALL required)
• FAERS analytics tools: ALL require operation parameter
• FAERS count tools: Use medicinalproduct NOT drug_name
• OpenTargets tools: Return nested {data: {entity: {field: ...}}} structure
• PubMed_search_articles: Returns plain list of dicts, NOT {articles: [...]}
• ReactomeAnalysis_pathway_enrichment: Takes space-separated identifiers string, NOT array
• ensembl_lookup_gene: REQUIRES species='homo_sapiens' parameter

Full tool parameter reference and response structures: TOOL_REFERENCE.md

Fallback Strategies

When a tool fails, try the next in chain before reporting "no data":

• 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 -> ClinicalTrials_search_studies -> PubMed clinical
• Safety: FAERS + FDA -> OpenTargets AEs -> DrugBank safety
• Literature: PubMed search -> EuropePMC search -> OpenTargets publications

Reference Files

• ANALYSIS_PROCEDURES.md - Full code examples for each phase
• REPORT_TEMPLATE.md - Markdown template for final report output
• SCORING_REFERENCE.md - Detailed scoring rubric and computation method
• TOOL_REFERENCE.md - Tool signatures, response structures, troubleshooting
• USE_PATTERNS.md - Common analysis patterns and edge case strategies
• QUICK_START.md - Quick-start guide with minimal examples

Related Skills

• tooluniverse-drug-repurposing - Drug repurposing without network analysis
• tooluniverse-drug-target-validation - Target validation
• tooluniverse-adverse-event-detection - Adverse event detection
• tooluniverse-systems-biology - Systems biology
• tooluniverse-protein-interactions - Protein interactions