3L3L

PARP complexed with A906894

Summary for 3L3L

• Entry DOI: 10.2210/pdb3l3l/pdb
• Related: 2RCW 2RD6 3GJW 3GN7
• Descriptor: Poly [ADP-ribose] polymerase 1, 3-oxo-2-piperidin-4-yl-2,3-dihydro-1H-isoindole-4-carboxamide (3 entities in total)
• Functional Keywords: protein-inhibitor complex, adp-ribosylation, dna damage, dna repair, dna-binding, glycosyltransferase, metal-binding, nad, nucleus, phosphoprotein, transcription, transcription regulation, transferase, transferase-transferase inhibitor complex, transferase/transferase inhibitor
• Biological source: Homo sapiens (human)
• Cellular location: Nucleus: P09874
• Total number of polymer chains: 1
• Total formula weight: 39428.11

Authors

Park, C.H. (deposition date: 2009-12-17, release date: 2010-12-22, Last modification date: 2024-04-03)

Primary citation

Gandhi, V.B.,Luo, Y.,Liu, X.,Shi, Y.,Klinghofer, V.,Johnson, E.F.,Park, C.,Giranda, V.L.,Penning, T.D.,Zhu, G.D.
Discovery and SAR of substituted 3-oxoisoindoline-4-carboxamides as potent inhibitors of poly(ADP-ribose) polymerase (PARP) for the treatment of cancer.
Bioorg.Med.Chem.Lett., 20:1023-1026, 2010

PubMed Abstract: Through conformational restriction of a benzamide by formation of a seven-membered hydrogen-bond with an oxindole carbonyl group, a series of PARP inhibitors was designed for appropriate orientation for binding to the PARP surface. This series of compounds with a 3-oxoisoindoline-4-carboxamide core structure, displayed modest to good activity against PARP-1 in both intrinsic and cellular assays. SAR studies at the lactam nitrogen of the pharmacophore have suggested that a secondary or tertiary amine is important for cellular potency. An X-ray structure of compound 1e bound to the protein confirmed the formation of a seven-membered intramolecular hydrogen bond. Though revealed previously in peptides, this type of seven-membered intramolecular hydrogen bond is rarely observed in small molecules. Largely due to the formation of the intramolecular hydrogen bond, the 3-oxoisoindoline-4-carboxamide core structure appears to be planar in the X-ray structure. An additional hydrogen bond interaction of the piperidine nitrogen to Gly-888 also contributes to the binding affinity of 1e to PARP-1.

PubMed: 20045315
DOI: 10.1016/j.bmcl.2009.12.042

Experimental method

X-RAY DIFFRACTION (2.5 Å)