Untapped Potential of Disordered Proteins in Current Druggable Human Proteome

可药性 蛋白质组 内在无序蛋白质 人类蛋白质组计划 计算生物学 药物发现 药品 生物 药物开发 纳米技术 生物信息学 蛋白质组学 生物化学 材料科学 药理学 基因
作者
Gang Hu,Zhonghua Wu,Kui Wang,Vladimir N. Uversky,Lukasz Kurgan
出处
期刊:Current Drug Targets [Bentham Science]
卷期号:17 (10): 1198-1205 被引量:58
标识
DOI:10.2174/1389450116666150722141119
摘要

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. Keywords: Disorder in disorders, druggable human proteome, intrinsic disorder, intrinsically disordered proteins, human drug target, rational drug design.

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