Hu Gang, Wu Zhonghua, Wang Kui, Uversky Vladimir N, Kurgan Lukasz
Department of Molecular Medicine, University of South Florida, 12901 Bruce B. Downs Blvd. MDC07, Tampa, Florida 33612, USA.
Curr Drug Targets. 2016;17(10):1198-205. doi: 10.2174/1389450116666150722141119.
Current efforts in design and characterization of drugs often rely on the structure of their protein targets. However, a large fraction of proteins lack unique 3-D structures and exist as highly dynamic structural ensembles. These intrinsically disordered proteins are involved in pathogenesis of various human diseases and are highly abundant in eukaryotes. Based on a comprehensive analysis of the current druggable human proteome covering 12 drug classes and 18 major classes of drug targets we show a significant bias toward high structural coverage and low abundance of intrinsic disorder. We review reasons for this bias including widespread use of the structural information in various stages of drug development and characterization process and difficulty with attaining structures for the intrinsically disordered proteins. We also discuss future of intrinsically disordered proteins as drug targets. Given the overall high disorder content of the human proteome and current bias of the druggable human proteome toward structural proteins, it is inevitable that disordered proteins will have to raise up on the list of prospective drug targets. The protein disorder-assisted drug design can draw from current rational drug design techniques and would also need novel approaches that no longer rely on a unique protein structure.
目前在药物设计和特性描述方面所做的努力通常依赖于其蛋白质靶点的结构。然而，很大一部分蛋白质缺乏独特的三维结构，而是以高度动态的结构集合体形式存在。这些内在无序蛋白质参与了多种人类疾病的发病过程，并且在真核生物中含量丰富。基于对涵盖12类药物和18类主要药物靶点的当前可成药人类蛋白质组的全面分析，我们发现存在明显偏向于高结构覆盖率和低内在无序丰度的情况。我们回顾了这种偏向的原因，包括在药物开发和特性描述过程的各个阶段广泛使用结构信息以及获得内在无序蛋白质结构的困难。我们还讨论了内在无序蛋白质作为药物靶点的未来。鉴于人类蛋白质组总体上无序含量较高，以及当前可成药人类蛋白质组对结构蛋白的偏向，无序蛋白质必然会在潜在药物靶点列表中占据更重要的位置。蛋白质无序辅助药物设计可以借鉴当前的合理药物设计技术，也将需要不再依赖于独特蛋白质结构的新方法。
