Poster Presentation The 44th Lorne Conference on Protein Structure and Function 2019

Intrinsic Fluorescence Spectroscopy And Molecular Modelling Lead To The Development Of New Tyrosyl-DNA Phosphodiesterase 1​ Inhibitors (#118)

Jinal Patel 1 , Konstantin Volcho 2 3 , Jóhannes Reynisson Reynisson 1 , IVANHOE LEUNG 1
  1. The University of Auckland, Auckland, NOT US OR CANADA, New Zealand
  2. N.N. Vorozhtsov Novosibirsk Institute of Organic Chemistry, Siberian Branch of the Russian Academy of Science, Novosibirsk, Russian Federation, Russia
  3. Department of Natural Sciences and Institute of Medicine and Psychology, Novosibirsk State University, Novosibirsk, Russian Federation, Russia

Human tyrosyl-DNA phosphodiesterase 1 (TDP1) is a DNA repair enzyme that mends topoisomerase 1-mediated DNA damage. TDP1 is a current inhibition target for the development of improved anticancer treatments, as its inhibition may enhance the therapeutic effect of topoisomerase 1 poisons.
The development of new TDP1 inhibitors would benefit from an efficient screening assay. As there are four tryptophan residues that are close to the substrate binding pocket of TDP1 (within 3-8 Å), we reasoned that the intrinsic fluorescence technique will be useful for the studies of TDP1-ligand binding interactions.
In the poster, we will report our results in the development and application of the intrinsic fluorescence technique to screen and quantify TDP1-ligand binding interactions. Operating this new assay in tandem with molecular modelling has led to the discovery of several new TDP1 inhibitors.