Structure-Based Binding Pocket Detection and Druggability Assessment

SANTIAGO RODRÍGUEZ; JUAN I. ALICE; CAROLINA L.BELLERA; ALAN TALEVI

Drug Target Selection and Validation

Springer Nature Switzerland

Año: 2022; p. 14 - 257

Target-focused (often described as “rational”) drug discovery starts with the identification and validation of one or more target biomolecules whose modulation will interfere with disease progression, or at least alleviate disease symptoms. In addition to verifying the association between such biomolecules and the disease, target validation often involves the assessment of some relevant properties, druggability among them.Druggability is often defined as the ability of a target to bind a small, drug-like molecule with high affinity and specificity. If a small molecule has already been reported to bind to a target in a specific manner, the target is traditionally regarded as druggable (recently, thus, it has been proposed that different targets might present different degrees of druggability, with some of them being “easy to drug” and some of them being “difficult to drug”). Druggability has also been implied based on evolutionary relationships (using a sort of transitivity or “guilt by association” principle), or by predicting druggable pockets from different levels of structural information, without comparison with any template. The latter approximations, which will invariably depart from the detection of binding pockets and later assign a score to differentiate druggable from non-druggable proteins, are the scope of the present chapter.Importantly, current methods to assess target druggability from structural data might be challenged by the occurrence of hidden or cryptic binding sites, which could more appropriately be assessed by studying the target dynamically, rather than from static representations of the biomolecule of interest.