Reverse Pharmacology: Target-Based Drug Discovery from Target to Molecule

Reverse pharmacology (target-based drug design) starts with a validated therapeutic target (protein, enzyme, receptor) and identifies/optimizes molecules that modulate it.

Workflow

1. Target identification & validation: Genetic, biochemical, phenotypic evidence linking target to disease.
2. Assay development: Biochemical (binding, enzymatic) or cell-based functional assay.
3. Hit identification: High-throughput screening (HTS), fragment-based screening, virtual screening (structure-based), or de novo design.
4. Hit-to-lead: Optimize potency, selectivity, ADME, safety.
5. Lead optimization: Balance efficacy, pharmacokinetics, toxicity, manufacturability.
6. Preclinical candidate selection: IND-enabling studies.

Contrast: Forward (Classical) Pharmacology

• Phenotypic screening → target deconvolution.
• Less hypothesis-driven; can find novel mechanisms.

Successes

• Imatinib (Gleevec) – BCR-ABL
• Gefitinib (Iressa) – EGFR
• Erlotinib (Tarceva) – EGFR
• Vemurafenib – BRAF V600E

Reverse pharmacology dominates modern drug discovery when target biology is clear.