Discovery of selective inhibitors of tyrosyl-DNA phosphodiesterase 2 by targeting the enzyme DNA-binding cleft.
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.
Department of Chemistry, Center for Diagnostics and Therapeutics, Georgia State University, Atlanta, GA 30302, United States.
Bradley R
BR
Kossmann
Developmental Therapeutics Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892, United States.
Monica
M
Abdelmalak
Developmental Therapeutics Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892, United States.
Sophia
S
Lopez
Developmental Therapeutics Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892, United States.
Gabrielle
G
Tender
Department of Chemistry, Center for Diagnostics and Therapeutics, Georgia State University, Atlanta, GA 30302, United States.
Chunli
C
Yan
Developmental Therapeutics Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892, United States.
Yves
Y
Pommier
Developmental Therapeutics Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892, United States. Electronic address: marchanc@mail.nih.gov.
Christophe
C
Marchand
Department of Chemistry, Center for Diagnostics and Therapeutics, Georgia State University, Atlanta, GA 30302, United States. Electronic address: iivanov@gsu.edu.
Ivaylo
I
Ivanov
D000818:Animals; D004268:DNA-Binding Proteins; D004305:Dose-Response Relationship, Drug; D055808:Drug Discovery; D006801:Humans; D051379:Mice; D056004:Molecular Dynamics Simulation; D015394:Molecular Structure; D009687:Nuclear Proteins / Q000037:antagonists & inhibitors* / Q000378:metabolism; D010726:Phosphodiesterase Inhibitors / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D010727:Phosphoric Diester Hydrolases / Q000378:metabolism; D013329:Structure-Activity Relationship; D014157:Transcription Factors / Q000037:antagonists & inhibitors* / Q000378:metabolism; D047988:Tumor Necrosis Factor Receptor-Associated Peptides and Proteins / Q000037:antagonists & inhibitors* / Q000378:metabolism; D015027:Zebrafish
D004268:DNA-Binding Proteins; D009687:Nuclear Proteins; D010726:Phosphodiesterase Inhibitors; D014157:Transcription Factors; D047988:Tumor Necrosis Factor Receptor-Associated Peptides and Proteins; D010727:Phosphoric Diester Hydrolases; C474866:TDP2 protein, human; C576816:TDP2 protein, mouse
Inhibitor; Rational drug design; TDP2; Tyrosyl-DNA phosphodiesterase 2; Virtual screening