Discovery of selective inhibitors of tyrosyl-DNA phosphodiesterase 2 by targeting the enzyme DNA-binding cleft

BIOORGANIC & MEDICINAL CHEMISTRY LETTERS

卷:26

Article

Kossmann, Bradley R.¹  Abdelmalak, Monica²  Lopez, Sophia²  Tender, Gabrielle²  Yan, Chunli¹  Pommier, Yves²  Marchand, Christophe²  Ivanov, Ivaylo¹ 

[1] Georgia State Univ, Dept Chem, Ctr Diagnost & Therapeut, Atlanta, GA 30302 USA

[2] NCI, Dev Therapeut Branch, Ctr Canc Res, NIH, Bethesda, MD 20892 USA

关键词: Tyrosyl-DNA phosphodiesterase 2;    TDP2;    Inhibitor;    Virtual screening;    Rational drug design;   

DOI  :  10.1016/j.bmcl.2016.05.065

来源: Elsevier

【 摘 要 】

Tyrosyl-DNA phosphodiesterase 2 (TDP2) processes protein/DNA adducts resulting from abortive DNA topoisomerase II (Top2) activity. TDP2 inhibition could provide synergism with the Top2 poison class of chemotherapeutics. By virtual screening of the NCI diversity small molecule database, we identified selective TDP2 inhibitors and experimentally verified their selective inhibitory activity. Three inhibitors exhibited low-micromolar IC50 values. Molecular dynamics simulations revealed a common binding mode for these inhibitors, involving association to the TDP2 DNA-binding cleft. MM-PBSA per-residue energy decomposition identified important interactions of the compounds with specific TDP2 residues. These interactions could provide new avenues for synthetic optimization of these scaffolds. (C) 2016 Elsevier Ltd. All rights reserved.

【 授权许可】

Free