Structure-based design, synthesis, and evaluation of inhibitors with high selectivity for PARP-1 over PARP-2

Design and synthesis of benzodiazepines as brain penetrating PARP-1 inhibitors

“…According to our previous study 42 , three key amino acids in PARP-1 (GLN759, GLU763, ASP766) were found, which formed an acidic cavity and specifically contained the hydrophilic group. Therefore, compounds containing exposed amino groups were synthesised to match the acidic domain of the PARP-1 active pocket ( Table 3 ).…”

Advances in Development of Selective Antitumor Inhibitors That Target PARP-1

“…The lactam group has become an essential pharmacophore for the design of PARP-1 inhibitors. 68 Building on the observations of Papeo et al, 59 Yu et al 69 conducted an analysis of disparities in essential amino acid residues located near the active sites of both PARP-1 and PARP-2 through alignment operations. This investigation revealed distinct spatial orientations of the partial α-helices of PARP-1 and PARP-2.…”

In Silico Mixed Ligand/Structure-Based Design of New CDK-1/PARP-1 Dual Inhibitors as Anti-Breast Cancer Agents

“…Figure 4a shows the PARP-1 catalytic domain, highlighting the main residues Gln 759 , Glu 763 , Asp 766 , Asn 767 , Gly 863 , Tyr 896 , Ala 898 , Ser 904 , and Tyr 907 (highly responsible for the stability of the binding pocket), Gly 863 and Ser 904 (which form a hydrogen bond network with the nicotinamide moiety), Glu 988 (catalytically important residue), Asp 770 and Arg 878 (critical in stabilizing the adenosine portion of the substrate NAD + ), and Tyr 907 (which forms a planar surface) [95][96][97] (Figure 4b). On the other hand, PARP-1 is structurally divided in three domains: the N-terminal DNA-binding domain (with three Zinc finger) [91], the central auto-modification domain (with specific glutamate and lysine residues as acceptors of ADP-ribose moieties) [92], and the C-terminal catalytic domain, which utilizes nicotinamide adenine dinucleotide (NAD + ) as a substrate to construct polymers of ADP-ribose on histones.…”