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The PARP family consists of 17 members with diverse functions, including those related to cancer cells’ viability. In particular, PARP-1 is involved in elimination of single- and double-strand breaks of DNA and responsible for cancer cell resistance to DNA-damaging chemotherapeutic agents, and PARP-5 modifies the axin protein in the Wnt pathway to promote cell proliferation. Several PARP-1 inhibitors (e.g., olaparib) have been recently approved and positioned as innovative anticancer drugs. However, they exert severe adverse effects, probably because of a low selectivity towards PARP-1 over other PARPs. An immediate challenge in medicinal chemistry is to develop more selective and safe PARP inhibitors. The design of effective PARP inhibitors is focused on targeting a region of the active site responsible for the NAD+ nicotinamide binding, and the aim of the present study was to compare this region in PARP 1–16 proteins and identify amino acid residues important for the selective interaction.