Structure-based view of the druggable genome.

Area of Science:

• Biochemistry
• Pharmacology
• Genomics

Background:

• International initiatives aim to create chemical probes for specific protein families.
• The 'Target 2035' initiative calls for comprehensive chemical coverage of the druggable human genome.
• Defining the 'druggable genome' is crucial for guiding drug discovery efforts.

Purpose of the Study:

• To systematically review protein structures bound to drug-like ligands in the Protein Data Bank (PDB).
• To establish a druggability metric using ligand desolvation upon binding.
• To map the landscape of the human druggable genome and identify potential targets for chemical probe development.

Main Methods:

• Systematic review of protein-ligand structures from the Protein Data Bank (PDB).
• Utilizing ligand desolvation energy as a key metric for assessing protein druggability.
• Analysis of protein families and their association with disease and existing small-molecule ligands.

Main Results:

• The majority of druggable protein families, including disease-associated ones, have few or no known small-molecule ligands.
• A landscape of the human druggable genome was generated based on structural data and druggability metrics.
• Identified 46 druggable domains, encompassing 3440 human proteins, as high-priority targets for future chemical probe discovery.

Conclusions:

• Significant gaps exist in small-molecule ligand coverage for many druggable protein families.
• The study provides a data-driven framework for prioritizing targets in chemical probe discovery.
• Focusing on the identified 46 druggable domains could accelerate the development of novel therapeutics.