Shifting from the single to the multitarget paradigm in drug discovery

Abstract

Increasing evidence that several drug compounds exert their effects through interactions with multiple targets is boosting the development of research fields that challenge the data reductionism approach. In this article, we review and discuss the concepts of drug repurposing, polypharmacology, chemogenomics, phenotypic screening and high-throughput in vivo testing of mixture-based libraries in an integrated manner. These research fields offer alternatives to the current paradigm of drug discovery, from a one target-one drug model to a multiple-target approach. Furthermore, the goals of lead identification are being expanded accordingly to identify not only 'key' compounds that fit with a single-target 'lock', but also 'master key' compounds that favorably interact with multiple targets (i.e. operate a set of desired locks to gain access to the expected clinical effects).

Figure 1

[LM1]Schematic representation of the single-target and multitarget drug discovery paradigms. Although one ligand (key) compound might fit and operate a single target (lock), diseases are associated with complex biological processes and, in several cases, with multiple targets, which are more difficult to ‘unlock’.

Figure 2

[LM2]Schematic representation of the relations between the concepts reviewed in this article. The table represents the association between all possible molecules in chemical space (rows) (organized in different types of chemical library), and targets in the ‘target space’ (columns) (collected in different types of target). The red circles indicate that there exists a compound–target interaction, whereas the black circles denote that there is no interaction. Empty cells indicate that the intersecting compound–target interaction is not known. Abbreviation: HTS, high throughput screening.

Figure 3

Schematic representation of in vivo high throughput screening (HTS) of mixture-based libraries. A representative core scaffold of mixture-based libraries is shown. The assay directly points to the hit compounds that might act through the interaction with multiple targets (‘master key’ compounds), which are readily identified after deconvolution.