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September 29, 2010
VIP: Target Profiling of a Small Library of Phosphodiesterase 5 (PDE5) Inhibitors using Chemical Proteomics
Reinout Raijmakers, Poupak Dadvar, Sarah Pelletier, Joost Gouw, Klaus Rumpel, and Albert J. R. Heck*
Over the past few decades, drug development efforts have optimized the ways in which one can gauge the effects that changes in a given compound's structure can have toward its biological target, thanks to activity assays and increased access to structural data. However, steering clear of off-target effects remains a significant challenge, because one small change to a drug can unpredictably alter its interaction profile toward a whole host of proteins.
Heck and colleagues used a semiquantitative chemical proteomics approach based on LC–MS–MS techniques to enrich for proteins that bind to analogues of the PDE5 inhibitors sildenafil and vardenafil. They synthesized a small library of four inhibitors using the structure of known PDE5 inhibitors as a scaffold, and evaluated their inhibitory potency towards PDE5 and related proteins. They next assessed the binding of a large set of proteins to these inhibitors and thus determined individual in vitro selectivity profiles for the inhibitors.
Their results show that even slight chemical modifications to these compounds can significantly bias their selectivity toward other interacting proteins. This opens the potential for the use of these compounds as scaffolds in the development of inhibitors for new protein targets. Their approach itself has the potential to be developed into a valuable tool for designing out undesired off-target interactions in vivo and for discovering new targets of established drug molecules as well.
Received July 22, 2010; published online September 22, 2010, DOI: 10.1002/cmdc.201000303.