Bioinformatic Analysis of the Nicotinamide Binding Site in Poly(ADP-Ribose) Polymerase Family Proteins

SIMPLE SUMMARY: The PARP family consists of 17 proteins, and some of them are responsible for cancer cells’ viability. Much attention is therefore given to the search for chemical compounds with the ability to suppress distinct PARP family members (for example, PARP-5a and 5b). Here, we present the results of a family-wide bioinformatic analysis of an important functional region in the PARP structure and describe factors that can guide the design of highly selective compounds. ABSTRACT: The PARP family consists of 17 members with diverse functions, including those related to cancer cells’ viability. Several PARP inhibitors are of great interest as innovative anticancer drugs, but they have low selectivity towards distinct PARP family members and exert serious adverse effects. We describe a family-wide study of the nicotinamide (NA) binding site, an important functional region in the PARP structure, using comparative bioinformatic analysis and molecular modeling. Mutations in the NA site and D-loop mobility around the NA site were identified as factors that can guide the design of selective PARP inhibitors. Our findings are of particular importance for the development of novel tankyrase (PARPs 5a and 5b) inhibitors for cancer therapy.