Structural coverage of the proteome for pharmaceutical applications

•Structural coverage has long been a hurdle to structure-based proteome-wide screens.•Current coverage nears 70% for the human proteome, 95% for human drug targets.•50% of human proteins are covered by four or more homologous structures.•Nearly any protein is capable of binding small-molecule drugs.•Insufficient structural coverage is a fading issue for drug discovery. Structure-based computational drug discovery efforts have traditionally focused on the structure of a single, well-known drug target. Important applications, such as target deconvolution and the analysis of polypharmacology, require proteome-scale molecular docking and have been inaccessible to structure-based in silico approaches. One important reason for this inaccessibility was that the structure of most proteins was not known. Lately, this ‘structure gap’ has been closing rapidly, and proteome-scale molecular docking seems within reach. Here, we survey the current state of structural coverage of the human genome and find that coverage is truly proteome-wide, both overall and in most pharmaceutically relevant categories of proteins. The time is right for structure-based approaches to target deconvolution and polypharmacology.