Discovery of Potent Tyrosyl-DNA Phosphodiesterase 1 Inhibitors Using in silico Virtual Screening & Network Analysis for Evolution of Allosteric Communication in 3-ketosteroid Receptors

Abstract

Tyrosyl-DNA phosphodiesterase I (TDP1) plays an important role in repair of topoisomerase I-DNA complexes in vivo, and its inhibitors have the potential to enhance the efficacy of the Top1-targeting drugs in anticancer therapy. Nevertheless a large number of TDP1 inhibitors have been reported, none of them has inhibition activity in vivo. We present a virtual screening protocol to explore potent TDP1-selective inhibitors. 3-ketosteroid receptors belong to nuclear receptor family, and their DNA binding domains interact with glucocorticoid response elements (GREs) to regulate gene transcription. With evolution, all of them can bind to activating response element ((+)GRE), but only some exhibit the ability to bind to negative glucocorticoid response element (nGRE). It was found that evolutionary mutations are important to change their binding functions. We have presented dynamic network models to elucidate allosteric communication for selected evolutionary homologues, discussing the correlation between binding characteristics and epistatic mutations from network theory