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.

传统上，基于结构的计算药物发现工作一直专注于单个知名药物靶标的结构。重要的应用，例如靶标反褶积和多药理学分析，需要蛋白质组规模的分子对接，并且基于结构的计算机无法访问方法。这种不可及的重要原因是大多数蛋白质的结构未知。最近，这种“结构缺口”已经迅速缩小，蛋白质组学规模的分子对接似乎可以实现。在这里，我们调查了人类基因组结构覆盖的当前状态，发现覆盖范围确实是蛋白质组范围的，无论是在蛋白质的整体上还是在大多数与药物相关的类别中。现在是采用基于结构的方法进行目标去卷积和多药理学研究的时候了。