Poly(ADP-ribose)polymerases (PARPs) catalyze a post-transcriptional modification of proteins, consisting in
the attachment of mono, oligo or poly ADP-ribose units from NAD+ to specific polar residues of target proteins. The scientific
interest in members of this superfamily of enzymes is continuously growing since they have been implicated in a
range of diseases including stroke, cardiac ischemia, cancer, inflammation and diabetes.
Despite some inhibitors of PARP-1, the founder member of the superfamily, have advanced in clinical trials for cancer
therapy, and other members of PARPs have recently been proposed as interesting drug targets, challenges exist in understanding
the polypharmacology of current PARP inhibitors as well as developing highly selective chemical tools to unravel
specific functions of each member of the superfamily.
Beginning with an overview on the molecular aspects that affect polypharmacology, in this article we discuss how these
may have an impact on PARP research and drug discovery. Then, we review the most selective PARP inhibitors hitherto
reported in literature, giving an update on the molecular aspects at the basis of selective PARP inhibitor design. Finally,
some outlooks on current issues and future directions in this field of research are also provided.