Development of a Rule-Based Method for the Assessment of Protein Druggability

Target selection is a critical step in the majority of
modern drug discovery programs. The viability of a drug target depends
on two components: biological relevance and chemical tractability.
The concept of druggability was introduced to describe the second
component, and it is defined as the ability of a target to bind a
drug-like molecule with a therapeutically useful level of affinity.
To investigate the rules that govern druggability, we developed an
algorithm to isolate and characterize the binding pockets of protein
targets. Using this algorithm, we performed a comparative analysis
between the relevant pockets of 60 targets of approved drugs and a
diverse set of 440 ligand-binding pockets. As a result, we defined
a preferred property space for druggable pockets based on five key
properties (volume, depth, enclosure, percentage of charged residues
and hydrophobicity), and we represented it with a set of simple rules.
These rules may be applicable in the future to evaluate the chemical
tractability of prospective targets.