What is Target Identification?
Target identification is the first and foundational step in the drug discovery process. It involves recognizing a biological entity—typically a gene, protein, or pathway—that plays a critical role in the onset or progression of a disease. The goal is to find a “druggable” target whose modulation can yield therapeutic benefits.
Basic Concepts
- Biological Targets: Proteins, genes, RNA molecules, and signaling pathways.
- Disease Association: Targets must be causally linked to disease mechanisms.
- Druggability: A target is druggable if it has a binding site suitable for small molecules or biologics.
Intermediate Concepts
- Target Validation: Experimental confirmation using gene editing, overexpression, and pharmacological inhibition.
- Omics Technologies: Genomics, transcriptomics, proteomics, and metabolomics for target discovery.
- Bioinformatics & Systems Biology: Use of databases and network analysis to predict and prioritize targets.
Advanced Concepts
- Functional Genomics: High-throughput CRISPR screens and synthetic lethality studies.
- Single-Cell Technologies: Single-cell RNA-seq and spatial transcriptomics.
- AI and Machine Learning: Predicting target-disease associations and integrating multi-omics data.
- Structural Biology: X-ray crystallography, Cryo-EM, and NMR for rational drug design.
- Phenotypic Screening: Reverse pharmacology and observable cellular responses.
Challenges in Target Identification
- Biological complexity and pathway redundancy
- Off-target effects and unintended interactions
- Tissue specificity and relevance
- Resistance mechanisms in cancer and infectious diseases
Real-World Examples
- BCR-ABL in CML: Led to imatinib (Gleevec), revolutionizing cancer therapy.
- PCSK9 in hypercholesterolemia: Monoclonal antibodies for lipid management.
- PD-1/PD-L1 in immuno-oncology: Immune checkpoint inhibitors like pembrolizumab.
Future Directions
- Targeting the “undruggable” such as transcription factors
- Allosteric modulation and alternative binding sites
- Microbiome-derived molecule targeting
- Precision targeting using patient-specific data