Protein-DNA interactions in disease and drug discovery

Abstract

Protein-DNA interactions are essential to all eukaryotes and are often involved in disease onset, progression and severity of or defence against them. However, their use in drug targetting has remained challenging due many reasons such as electrostatic and non-specific interactions of omnipresent DNA backbone. Yet, protein-DNA interactions including regulatory transcriptional events and pathogen-sensing by host have remained critical in drug discovery and their potential as direct drug targets has been increasingly recognised. In this review article, we take a survey of three key aspects of protein-DNA interactions namely transcription, replication and repair, and genome organization, whose misregulation has been implicated in diseases and used as therapeutic targets. We provide a comprehensive list of targets and drugs, which have been used in drug discovery and in which discovery process has reached clinical trial or approval stage. We also review the computational methods, including AI powering these developments. We observe that, despite a general notion of protein-DNA interactions being treated as undruggable, literature shows that a time to use them as effective targets has come, highlighted by a growing number of candidate drugs in each category.