Multitarget Drug Discovery


The multifunctional nature of currently incurable diseases has provided a strong background for the development of an innovative drug discovery strategy centred around the concepts of polypharmacology and dubbed multitarget drug discovery. It deals with the development of multitarget‐directed‐ligands (MTDLs), that is individual small molecules that, by simultaneously hitting multiple targets, should be able to tackle the compensatory mechanisms and robustness of complex disease networks, with the intrinsic benefits of a single‐molecule therapy. Starting from the 2000, multitarget drug discovery has emerged as an attractive alternative to the traditional single‐target approach. The elaboration of rationale medicinal chemistry strategies has allowed the discovery of already‐approved multitarget drugs and of many others that are in diverse development stages. It may thus become a constant feature of future drug discovery.

Key Concepts

  • One‐drug one‐target one‐disease paradigm has been dominating but is seen to have limitations.
  • The multifactorial nature of diseases supports the development of treatments able to modulate more than one target simultaneously, that is the so‐called polypharmacology.
  • There are three ways to achieve polypharmacology: drug cocktail, fixed‐dose combination, and multitarget‐drug.
  • Multitarget drugs can be superior to combinations thanks to a lower risk of drug–drug interactions and a simplification of the therapeutic regimen.
  • Multitarget drugs can be discovered either by rationale or by screening approaches.
  • Rationale approaches rely on the creation of hybrid drugs via linking, fusing and merging approaches.

Keywords: multitarget‐directed ligands; polypharmacology; rational drug design strategies; hybrid molecules; medicinal chemistry

Figure 1. Structures of imatinib, midostaurin, clozapine and safinamide multitarget drugs.
Figure 2. Possible clinical strategies for a polypharmacological therapy.
Figure 3. Design strategy for hybrid compounds.
Figure 4. Molecular examples of linking strategy: rational design of sultamicillin and edasalonexent.
Figure 5. Molecular example of the fused strategy: rational design of ladostigil.
Figure 6. Design of the dual BACE‐1/GSK‐3β inhibitors.


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Further Reading

Handler Norbert and Buschmann Helmut (2018) Drug Selectivity: An Enveloping Concept in Medicinal Chemistry: Weinheim, Germany.

Morphy J Richard and Harris C John (2012) Designing Multi‐Target Drugs: Cambridge, UK.

Peters Jens‐Uwe (2012) Polypharmacology in Drug Discovery: New Jersey, USA.

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Bolognesi, Maria L, and Rossi, Michele(Feb 2020) Multitarget Drug Discovery. In: eLS. John Wiley & Sons Ltd, Chichester. [doi: 10.1002/9780470015902.a0028845]