Sakharkar Meena K, Li Peng, Zhong Zhaowei, Sakharkar Kishore R
ADAMs Lab, Mechanical, Aerospace Engineering, Nanyang Technological University, Singapore.
Int J Biol Sci. 2007 Dec 10;4(1):15-22. doi: 10.7150/ijbs.4.15.
Accumulated knowledge of genomic information, systems biology, and disease mechanisms provide an unprecedented opportunity to elucidate the genetic basis of diseases, and to discover new and novel therapeutic targets from the wealth of genomic data. With hundreds to a few thousand potential targets available in the human genome alone, target selection and validation has become a critical component of drug discovery process. The explorations on quantitative characteristics of the currently explored targets (those without any marketed drug) and successful targets (targeted by at least one marketed drug) could help discern simple rules for selecting a putative successful target. Here we use integrative in silico (computational) approaches to quantitatively analyze the characteristics of 133 targets with FDA approved drugs and 3120 human disease genes (therapeutic targets) not targeted by FDA approved drugs. This is the first attempt to comparatively analyze targets with FDA approved drugs and targets with no FDA approved drug or no drugs available for them. Our results show that proteins with 5 or fewer number of homologs outside their own family, proteins with single-exon gene architecture and proteins interacting with more than 3 partners are more likely to be targetable. These quantitative characteristics could serve as criteria to search for promising targetable disease genes.
基因组信息、系统生物学和疾病机制方面的知识积累,为阐明疾病的遗传基础以及从海量基因组数据中发现新的治疗靶点提供了前所未有的机遇。仅在人类基因组中就有数百到数千个潜在靶点,靶点的选择和验证已成为药物研发过程的关键环节。对当前已探索靶点(尚无任何上市药物的靶点)和成功靶点(至少有一款上市药物针对的靶点)的定量特征进行探索,有助于找出选择潜在成功靶点的简单规则。在此,我们采用整合的计算机模拟方法,对133个有FDA批准药物的靶点和3120个未被FDA批准药物靶向的人类疾病基因(治疗靶点)的特征进行定量分析。这是首次对有FDA批准药物的靶点与无FDA批准药物或尚无针对它们的药物的靶点进行比较分析。我们的结果表明,在其家族外同源物数量为5个或更少的蛋白质、具有单外显子基因结构的蛋白质以及与3个以上伙伴相互作用的蛋白质更有可能成为可成药靶点。这些定量特征可作为寻找有前景的可成药疾病基因的标准。