Target class drug discovery

Abstract

Selection of molecular targets based on disease understanding is a dominant paradigm in drug discovery. We argue that a focus on classes of targets with central roles in biology provides a complementary approach that has higher quality outcomes in early discovery efforts.

Figure 1

The three principles of target class discovery. The purposeful design and construction of focused compound libraries based on structural and ligand similarities, often guided by available structural information, can effectively enable target class hit discovery when coupled with robust assay platforms that allow extensive cross-screening against a carefully chosen panel of representative proteins. Ultimately, a target class platform composed of these three interconnected principles will deliver high-quality ligands in a rational, systematic, and productive fashion with diminished chances for technical failure.

Figure 2

Overview of target class scaffold hopping and optimization. Evaluating proteins that are connected by their structural similarities or functional redundancies enables diverse ligand hypotheses to be tested against a set of related targets. Such ligand hypotheses can be the result of structure- or ligand-based design efforts. Alternatively, privileged scaffolds, which are known to have activity against one or more targets within the class, may be available and can serve as the basis for creating focused compound libraries that are likely to yield ligands of novel potencies and selectivity profiles. Screening a carefully chosen panel of related targets can also facilitate scaffold hopping when a hit for one target is shown to have affinity for another member of the family.