Protein-DNA interactions in disease and drug discovery

Protein-DNA interactions (PDIs) are fundamental to all organisms and are often involved in the onset, progression, and severity of diseases or in defence against them. However, their use in drug targeting has remained challenging due to many reasons, including the electrostatic and non-specific interactions of the omnipresent DNA backbone. Nevertheless, PDIs, including regulatory transcriptional events and pathogen-sensing by hosts, have remained critical in drug discovery, and their potential as direct drug targets has been increasingly recognised. In this review article, we survey three key aspects of PDIs in humans, namely transcription, replication-and-repair, and genome organisation, whose misregulation has been implicated in various diseases, thereby highlighting PDIs as viable therapeutic targets. We provide a comprehensive list of targets and drugs used in drug discovery, that have reached the clinical trial or approval stage. We also review the computational methods, including AI-based approaches, that are powering these developments. We observe that, despite the general notion of PDIs being treated as undruggable, the literature shows that the time to use them as effective targets has come, as reflected by the growing number of candidate drugs across these categories.