Much of biomedical research and therapeutic development focuses on a small fraction of the human proteome. Approximately 90% of approved drugs target enzymes, transporters, GPCRs, CD markers, voltage-gated ion channels and nuclear receptors. However, current estimates suggest that only 15% of disease-associated proteins can be readily targeted by FDA-approved therapeutics. Consequently, the vast majority of potential drug targets remain inaccessible to conventional chemical biology approaches.

Among other reasons, the limited ability to target the main binding site of potentially therapeutic proteins poses a significant challenge to traditional drug discovery approaches, with these targets often considered 'undruggable'.

However, alternative strategies such as targeting allosteric (remote) or cryptic (hidden) binding pockets present significant opportunities to expand the repertoire of druggable targets. In particular, cryptic binding pockets offer promising avenues for drug discovery even in the absence of other exploitable pockets.

This thesis provides an overview of the research field of cryptic pocket detection and its potential impact on drug discovery. It outlines the most promising methods for identifying cryptic pockets, with a particular emphasis on computational approaches. It also explores the functional roles and biological significance of cryptic sites and it presents current estimates of the number of known cryptic cavities.