Medicinal Polypharmacology in the Clinic – Translating the Polypharmacolome into Therapeutic Benefit

Abstract

Drugs with multiple targets, often annotated as ‘unselective’, ‘promiscuous’, ‘multitarget’, or ‘polypharmacological’, are widely considered in both academic and industrial research as a high risk due to the likelihood of adverse effects. However, retrospective analyses have shown that particularly approved drugs bear rich polypharmacological profiles. This raises the question whether our perception of the specificity paradigm (‘one drug-one target concept’) is correct – and if specifically multitarget drugs should be developed instead of being rejected. These questions provoke a paradigm shift – regarding the development of polypharmacological drugs not as a ‘waste of investment’, but acknowledging the existence of a ‘lack of investment’. This perspective provides an insight into modern drug development highlighting latest drug candidates that have not been assessed in a broader polypharmacology-based context elsewhere embedded in a historic framework of classical and modern approved multitarget drugs. The article shall be an inspiration to the scientific community to re-consider current standards, and more, to evolve to a better understanding of polypharmacology from a challenge to an opportunity.

Medicinal polypharmacology—a scientific glossary of terminology and concepts

“…The opportunity space of molecular interactions between the structural-biological limitation of target proteins ( Structural conservatism of nature ) and the molecular-structural limitation of multitarget ligands/small-molecule drugs ( Multitarget fingerprint ; Superpatterns ) ( Stefan and Rafehi, 2023 ; Rafehi et al, 2024 ).…”

“…This vastly growing research field, which we designated as “medicinal polypharmacology” ( Stefan and Rafehi, 2023 ; Rafehi et al, 2024 ), expands into various individual research fields, allowing for novel concepts to emerge. (i) The clinically observed effects of drugs are generally a result of multiple individual interactions with multiple interaction partners ( Paolini et al, 2006 ; Vulpetti et al, 2012 ; Jalencas and Mestres, 2013b ; Anighoro et al, 2014 ; Schmidt et al, 2014 ); (ii) Prevalent human diseases are often multifactorial with far-reaching disease networks that result in feedback, crosstalk, and, subsequently, therapy resistance ( Morphy and Rankovic, 2007 ; Azmi and Mohammad, 2014 ; Keith et al, 2005 ); (iii) Multitargeticity is an inherent character of small molecules that has molecular-structural limits ( Paolini et al, 2006 ; Hu and Bajorath, 2010 ; Jalencas and Mestres, 2013a ; Anighoro et al, 2014 ; Namasivayam et al, 2022a ); (iv) Phylogenetically distant proteins have common and reoccurring structural motifs [ Superfolds ( Orengo et al, 1994 ; Russell et al, 1998 ; Grishin, 2001 ; Koch, 2011 )] which can form Supersites that bind related, multitarget ligands ( Russell et al, 1998 ; Namasivayam et al, 2021a ); (v) The multitarget inheritance of multitarget drugs allows for superior clinical effectiveness and, in parallel, exploration of yet undruggable targets of the future [ Privileged ligands ( Jalencas and Mestres, 2013a ; Kim et al, 2014 ) and Target repurposing ( Paolini et al, 2006 ; Pollastri and Campbell, 2011 ; Klug et al, 2016 ; Singh et al, 2020 )].…”