Polypharmacology by Design: A Medicinal Chemist’s Perspective on Multitargeting Compounds

TLDR

Multitargeting compounds are increasingly important in drug discovery for complex diseases, offering additive or synergistic effects and reduced side effects, as exemplified by drugs such as aspirin. The authors analyze the relevance of multiple ligands in drug discovery and the toolbox for designing polypharmacology. They review modern in vitro assays, computational tools, crystallography, and fragment‑based design that enable systematic search for rational target combinations. Designed polypharmacology, though facing unresolved challenges, offers enormous potential for future therapeutic innovation.

Abstract

Multitargeting compounds comprising activity on more than a single biological target have gained remarkable relevance in drug discovery owing to the complexity of multifactorial diseases such as cancer, inflammation, or the metabolic syndrome. Polypharmacological drug profiles can produce additive or synergistic effects while reducing side effects and significantly contribute to the high therapeutic success of indispensable drugs such as aspirin. While their identification has long been the result of serendipity, medicinal chemistry now tends to design polypharmacology. Modern in vitro pharmacological methods and chemical probes allow a systematic search for rational target combinations and recent innovations in computational technologies, crystallography, or fragment-based design equip multitarget compound development with valuable tools. In this Perspective, we analyze the relevance of multiple ligands in drug discovery and the versatile toolbox to design polypharmacology. We conclude that despite some characteristic challenges remaining unresolved, designed polypharmacology holds enormous potential to secure future therapeutic innovation.