tooluniverse-drug-research

# Drug Research Strategy

Comprehensive drug investigation using 50+ ToolUniverse tools across chemical databases, clinical trials, adverse events, pharmacogenomics, and literature.

**KEY PRINCIPLES**:
1. **Report-first approach** - Create report file FIRST, then populate progressively
2. **Compound disambiguation FIRST** - Resolve identifiers before research
3. **Citation requirements** - Every fact must have inline source attribution
4. **Evidence grading** - Grade claims by evidence strength (T1-T4)
5. **Mandatory completeness** - All sections must exist, even if "data unavailable"
6. **English-first queries** - Always use English drug/compound names in tool calls, even if the user writes in another language. Only try original-language terms as a fallback. Respond in the user's language

---

## LOOK UP, DON'T GUESS

When asked about a drug, query ChEMBL/PubChem/DailyMed FIRST. Don't guess at mechanism, targets, or side effects — look them up. When you're not sure about a fact, your first instinct should be to SEARCH for it using tools, not to reason harder from memory.

---

## Drug Mechanism Reasoning

When investigating a drug's mechanism of action, trace the full causal chain:
1. **Target engagement** - Which protein(s) does the drug bind, and with what affinity/selectivity?
2. **Molecular effect** - Does binding inhibit, activate, or modulate the target's function?
3. **Pathway consequence** - Which signaling or metabolic pathway is altered downstream?
4. **Cellular phenotype** - What changes occur at the cell level (proliferation, apoptosis, secretion)?
5. **Physiological outcome** - How does the cellular effect translate to the therapeutic benefit in the patient?

---

## Workflow Overview

### 1. Report-First Approach (MANDATORY)

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

1. **Create the report file FIRST** - `[DRUG]_drug_report.md` with all 11 section headers and `[Researching...]` placeholders. See [REPORT_TEMPLATE.md](REPORT_TEMPLATE.md) for the full template.
2. **Progressively update the report** - Replace placeholders with findings as you query each tool.
3. **Use ALL relevant tools** - Query multiple databases for each data type; cross-reference across sources.

### 2. Citation Requirements (MANDATORY)

Every piece of information MUST include its source. Use inline citations:
```markdown
*Source: PubChem via `PubChem_get_compound_properties_by_CID` (CID: 4091)*
```

### 3. Progressive Writing Workflow

```
Step 1:  Create report file with all section headers
Step 2:  Resolve compound identifiers -> Update Section 1
Step 3:  Query PubChem/ADMET-AI/DailyMed SPL -> Update Section 2 (Chemistry)
Step 4:  Query FDA Label MOA + ChEMBL + DGIdb -> Update Section 3 (Mechanism)
Step 5:  Query ADMET-AI tools -> Update Section 4 (ADMET)
Step 6:  Query ClinicalTrials.gov -> Update Section 5 (Clinical)
Step 7:  Query FAERS/DailyMed -> Update Section 6 (Safety)
Step 8:  Query PharmGKB -> Update Section 7 (Pharmacogenomics)
Step 9:  Query DailyMed/Orange Book -> Update Section 8 (Regulatory)
Step 10: Query PubMed/literature -> Update Section 9 (Literature)
Step 11: Synthesize findings -> Update Executive Summary & Section 10
Step 12: Document all sources -> Update Section 11 (Data Sources)
```

---

## Compound Disambiguation (Phase 1)

**CRITICAL**: Establish compound identity before any research.

### Identifier Resolution Chain

```
1. PubChem_get_CID_by_compound_name(compound_name)
   -> Extract: CID, canonical SMILES, formula

2. ChEMBL_search_compounds(query=drug_name)
   -> Extract: ChEMBL ID, pref_name

3. DailyMed_search_spls(drug_name)
   -> Extract: Set ID, NDC codes (if approved)

4. PharmGKB_search_drugs(query=drug_name)
   -> Extract: PharmGKB ID (PA...)
```

### Handle Naming Ambiguity

| Issue | Example | Resolution |
|-------|---------|------------|
| Salt forms | metformin vs metformin HCl | Note all CIDs; use parent compound |
| Isomers | omeprazole vs esomeprazole | Verify SMILES; separate entries if distinct |
| Prodrugs | enalapril vs enalaprilat | Document both; note conversion |
| Brand confusion | Different products same name | Clarify with user |

---

## Research Paths Summary

Each path has detailed tool chains and output examples in [REPORT_GUIDELINES.md](REPORT_GUIDELINES.md).

### PATH 1: Chemical Properties & CMC
**Tools**: PubChem properties -> ADMET-AI physicochemical -> ADMET-AI solubility -> DailyMed chemistry/description
**Output**: Physicochemical table, Lipinski assessment, QED score, salt forms, formulation comparison

### PATH 2: Mechanism & Targets
**Tools**: DailyMed MOA -> ChEMBL activities (NOT `ChEMBL_get_molecule_targets`) -> ChEMBL target details -> DGIdb -> PubChem bioactivity
**Critical**: Derive targets from activities filtered to pChEMBL >= 6.0. Avoid `ChEMBL_get_molecule_targets`.
**Output**: FDA MOA text, target table with UniProt/potency, selectivity profile

### PATH 3: ADMET Properties
**Tools**: ADMET-AI (bioavailability, BBB, CYP, clearance, toxicity)
**Fallback**: DailyMed clinical_pharmacology + pharmacokinetics + drug_interactions
**Critical**: If ADMET-AI fails, automatically use fallback. Never leave Section 4 empty.

### PATH 4: Clinical Trials
**Tools**: search_clinical_trials -> compute phase counts -> extract outcomes/AEs -> fda_pharmacogenomic_biomarkers
**Critical**: Section 5.2 must show actual counts by phase/status in table format.

### PATH 5: Post-Marketing Safety
**Tools**: FAERS (reactions, seriousness, outcomes, deaths, age) + DailyMed (DDI, dosing, warnings)
**Critical**: Include FAERS date window, seriousness breakdown, and limitations paragraph.

### PATH 6: Pharmacogenomics
**Tools**: PharmGKB (search -> details -> annotations -> guidelines)
**Fallback**: DailyMed pharmacogenomics section + PubMed literature

### PATH 7: Regulatory & Patents
**Tools**: FDA Orange Book (search, approval history, exclusivity, patents, generics) + DailyMed (special populations via LOINC codes)
**Note**: US-only data; document EMA/PMDA limitation.

### PATH 8: Real-World Evidence
**Tools**: ClinicalTrials.gov (OBSERVATIONAL studies) + PubMed (real-world, registry, surveillance)

### PATH 9: Comparative Analysis
**Tools**: Abbreviated tool chains for each comparator + head-to-head trial search + PubMed meta-analyses

---

## FDA Label Core Fields

For approved drugs, retrieve these DailyMed sections early (after getting set_id):

| Batch | Sections | Maps to Report |
|-------|----------|---------------|
| Phase 1 | mechanism_of_action, pharmacodynamics, chemistry | Sections 2-3 |
| Phase 2 | clinical_pharmacology, pharmacokinetics, drug_interactions | Sections 4, 6.5 |
| Phase 3 | warnings_and_cautions, adverse_reactions, dosage_and_administration | Sections 6, 8.2 |
| Phase 4 | pharmacogenomics, clinical_studies, description, inactive_ingredients | Sections 5, 7 |

---

## Fallback Chains

| Primary Tool | Fallback | Use When |
|--------------|----------|----------|
| `PubChem_get_CID_by_compound_name` | `ChEMBL_search_drugs` | Name not in PubChem |
| `ChEMBL_get_molecule_targets` | **Use `ChEMBL_search_activities` instead** | Always avoid this tool |
| `ChEMBL_get_activity` | `PubChemBioAssay_get_assay_summary` | No ChEMBL ID |
| `DailyMed_search_spls` | `PubChemTox_get_acute_effects` | DailyMed timeout |
| `PharmGKB_search_drugs` | DailyMed PGx sections + PubMed | PharmGKB unavailable |
| `PharmGKB_get_dosing_guidelines` | DailyMed pharmacogenomics section | PharmGKB API error |
| `FAERS_count_reactions_by_drug_event` | Document "FAERS unavailable" + use label AEs | API error |
| `ADMETAI_*` (all tools) | DailyMed clinical_pharmacology + pharmacokinetics | Invalid SMILES or API error |

---

## Quick Reference: Tools by Use Case

| Use Case | Primary Tool | Fallback | Evidence |
|----------|--------------|----------|----------|
| Name -> CID | `PubChem_get_CID_by_compound_name` | `ChEMBL_search_drugs` | T1 |
| Properties | `PubChem_get_compound_properties_by_CID` | ADMET-AI physicochemical | T1/T2 |
| FDA MOA | `DailyMed_parse_clinical_pharmacology` (mechanism_of_action) | - | T1 |
| Targets | `ChEMBL_search_activities` -> `ChEMBL_get_target` | `DGIdb_get_drug_info` | T1 |
| ADMET | `ADMETAI_predict_*` (5 tools) | DailyMed PK sections | T2/T1 |
| Trials | `search_clinical_trials` | - | T1 |
| Trial outcomes | `extract_clinical_trial_outcomes` | - | T1 |
| FAERS | `FAERS_count_reactions_by_drug_event` | Label adverse_reactions | T1 |
| Dose mods | `DailyMed_parse_clinical_pharmacology` (dosage, warnings) | - | T1 |
| PGx | `PharmGKB_search_drugs` | DailyMed PGx + PubMed | T2/T1 |
| Label | `DailyMed_search_spls` | `PubChemTox_get_acute_effects` | T1 |
| Literature | `PubMed_search_articles` | `EuropePMC_search_articles` | Varies |
| Regulatory | `FDA_OrangeBook_*` tools | DailyMed label data | T1 |

See [TOOLS_REFERENCE.md](TOOLS_REFERENCE.md) for the complete tool listing with parameters and input format requirements.

---

## Type Normalization

Many tools require **string** inputs. Always convert IDs before API calls:
- ChEMBL IDs, PubMed IDs, NCT IDs: convert int -> str
- SMILES for ADMET-AI: pass as list `["SMILES_STRING"]`
- FAERS drug names: use UPPERCASE (e.g., `"METFORMIN"`)
- ChEMBL IDs: full format `"CHEMBL1431"` not `"1431"`
- PharmGKB IDs: PA prefix `"PA450657"` not `"450657"`

---

## Common Use Cases

| Use Case | Primary Sections | Light Sections |
|----------|------------------|----------------|
| Approved Drug Profile | All 11 sections | None |
| Investigational Compound | 1, 2, 3, 4, 9 | 5, 6, 7, 8 |
| Safety Review | 1, 5, 6, 7, 9 | 2, 3, 4, 8 |
| ADMET Assessment | 1, 2, 4 | 3, 5, 6, 7, 8, 9 |
| Clinical Development Landscape | 1, 5, 9 | 2, 3, 4, 6, 7, 8 |

Always maintain all section headers but adjust depth based on query focus and data availability.

---

## When NOT to Use This Skill

- **Target research** -> Use target-intelligence-gatherer skill
- **Disease research** -> Use disease-research skill
- **Literature-only** -> Use literature-deep-research skill
- **Single property lookup** -> Call tool directly
- **Structure similarity search** -> Use `PubChem_search_compounds_by_similarity` directly

---

## Cross-Skill References

For drug interaction checking, run: `python3 skills/tooluniverse-drug-drug-interaction/scripts/pharmacology_ref.py --type interaction --drug1 X --drug2 Y`

---

## Additional Resources

- **Report template**: [REPORT_TEMPLATE.md](REPORT_TEMPLATE.md) - Initial file template, citation format, evidence grading, scorecard, audit template
- **Report guidelines**: [REPORT_GUIDELINES.md](REPORT_GUIDELINES.md) - Detailed section-by-section instructions with output examples
- **Tool reference**: [TOOLS_REFERENCE.md](TOOLS_REFERENCE.md) - Complete tool listing with parameters and input formats
- **Verification checklist**: [CHECKLIST.md](CHECKLIST.md) - Section-by-section pre-delivery verification
- **Examples**: [EXAMPLES.md](EXAMPLES.md) - Detailed workflow examples for different use cases