This chapter will roughly follow the evolution of NAD+mimetic, catalytic- site PARP inhibitor designs aided by the use of co-crystal structures and modeling. Early co-crystal structures of the PARP catalytic domain (CD) established a well-defined and well-conserved hydrogen bonding motif at the nicotinamide binding site with the carboxamide functionality of the inhibitor, and multiple pi-type interactions between the inhibitor and catalytic site tyrosine residues. Larger PARP inhibitors have demonstrated extended binding into the adenine-ribose site. The structure based drug design (SBDD) and modeling initially focused on PARP-1 (ARTD1) and PARP-2 (ARTD2), and these are the most well described proteins in the literature. Other PARP CDs have recently been crystallized, and SBDD efforts towards tankyrase 1 (TNKS1, ARTD5) and 2 (TNKS2, ARDT6) inhibitors will be described.
CITATION STYLE
Canan, S. S. (2015). Structure based design of PARP inhibitors. Cancer Drug Discovery and Development, 83, 205–221. https://doi.org/10.1007/978-3-319-14151-0_8
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