Structural insights on the pamoic acid and the 8 kDa domain of DNA polymerase beta complex: Towards the design of higher-affinity inhibitors |
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Authors: | Corinne Hazan François Boudsocq Virginie Gervais Olivier Saurel Marion Ciais Christophe Cazaux Jerzy Czaplicki Alain Milon |
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Affiliation: | (1) University of Toulouse, UPS; IPBS (Institute of Pharmacology and Structural Biology), 205 route de Narbonne, 31077 Toulouse, France;(2) CNRS, IPBS, UMR5089, Toulouse, France |
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Abstract: | Background 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. |
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