Structural insights on the pamoic acid and the 8 kDa domain of DNA polymerase beta complex: towards the design of higher-affinity inhibitors.

BMC Structural Biology
Corinne HazanAlain Milon

Abstract

DNA polymerase beta (pol beta), the error-prone DNA polymerase of single-stranded DNA break repair as well as base excision repair pathways, is overexpressed in several tumors and takes part in chemotherapeutic agent resistance, like that of cisplatin, through translesion synthesis. For this reason pol beta has become a therapeutic target. Several inhibitors have been identified, but none of them presents a sufficient affinity and specificity to become a drug. The fragment-based inhibitor design allows an important improvement in affinity of small molecules. The initial and critical step for setting up the fragment-based strategy consists in the identification and structural characterization of the first fragment bound to the target. We have performed docking studies of pamoic acid, a 9 micromolar pol beta inhibitor, and found that it binds in a single pocket at the surface of the 8 kDa domain of pol beta. However, docking studies provided five possible conformations for pamoic acid in this site. NMR experiments were performed on the complex to select a single conformation among the five retained. Chemical Shift Mapping data confirmed pamoic acid binding site found by docking while NOESY and saturation transfer experiments prov...Continue Reading

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Citations

May 9, 2012·Drug Discovery Today·Khaled H BarakatJack A Tuszynski
Jan 5, 2011·Journal of Molecular Graphics & Modelling·Khaled Barakat, Jack Tuszynski
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Aug 11, 2020·Bioorganic & Medicinal Chemistry·Sasha M DaskalovaSidney M Hecht
Jun 24, 2009·Chemical Reviews·Mats Ljungman

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Methods Mentioned

BETA
X ray
NMR
Chemical
chemical shift

Software Mentioned

AutoDock
NMRView
pdbqs
GOSA
Pymol
NMRPipe
TOPSPIN
Linux

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