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

详细信息    查看全文

• 作者：Bradley R. Kossmann^a ; Monica Abdelmalak^b ; Sophia Lopez^b ; Gabrielle Tender^b ; Chunli Yan^a ; Yves Pommier^b ; Christophe Marchand^b ; ^{marchanc@mail.nih.gov" class="auth_mail" title="E-mail the corresponding author} ; Ivaylo Ivanov^a ; ^{iivanov@gsu.edu" class="auth_mail" title="E-mail the corresponding author}
• 关键词：Tyrosyl-DNA phosphodiesterase 2 ; TDP2 ; Inhibitor ; Virtual screening ; Rational drug design
• 刊名：Bioorganic & Medicinal Chemistry Letters
• 出版年：2016
• 出版时间：15 July 2016
• 年：2016
• 卷：26
• 期：14
• 页码：3232-3236
• 全文大小：764 K

文摘

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.