Department of Computer Science, University of Cincinnati, OH, USA.
Brief Bioinform. 2011 Jul;12(4):346-56. doi: 10.1093/bib/bbr021. Epub 2011 Apr 18.
The need and opportunity to discover therapeutics for rare or orphan diseases are enormous. Due to limited prevalence and/or commercial potential, of the approximately 6000 orphan diseases (defined by the FDA Orphan Drug Act as <200 000 US prevalence), only a small fraction (5%) is of interest to the biopharmaceutical industry. The fact that drug development is complicated, time-consuming and expensive with extremely low success rates only adds to the low rate of therapeutics available for orphan diseases. An alternative and efficient strategy to boost the discovery of orphan disease therapeutics is to find connections between an existing drug product and orphan disease. Drug Repositioning or Drug Repurposing--finding a new indication for a drug--is one way to maximize the potential of a drug. The advantages of this approach are manifold, but rational drug repositioning for orphan diseases is not trivial and poses several formidable challenges--pharmacologically and computationally. Most of the repositioned drugs currently in the market are the result of serendipity. One reason the connection between drug candidates and their potential new applications are not identified in an earlier or more systematic fashion is that the underlying mechanism 'connecting' them is either very intricate and unknown or indirect or dispersed and buried in an ever-increasing sea of information, much of which is emerging only recently and therefore is not well organized. In this study, we will review some of these issues and the current methodologies adopted or proposed to overcome them and translate chemical and biological discoveries into safe and effective orphan disease therapeutics.
发现治疗罕见病或孤儿病的疗法的需求和机会是巨大的。由于患病率有限和/或商业潜力，在大约 6000 种孤儿病（FDA 孤儿药法案定义为<200000 美国患病率）中，只有一小部分（5%）引起了生物制药行业的兴趣。药物开发复杂、耗时且昂贵，成功率极低，这使得孤儿病的治疗方法更加稀缺。一种替代的、有效的策略，可以促进罕见病治疗方法的发现，是在现有药物产品和孤儿病之间寻找联系。药物再定位或药物重新定位——为药物寻找新的适应症——是最大限度地发挥药物潜力的一种方法。这种方法有很多优点，但合理的孤儿病药物再定位并不简单，存在几个艰巨的挑战——药理学和计算方面。目前市场上的大多数再定位药物都是偶然发现的。候选药物与其潜在新应用之间的联系没有更早或更系统地确定的一个原因是，将它们联系在一起的潜在机制要么非常复杂和未知，要么是间接的、分散的，埋藏在不断增加的信息海洋中，其中大部分信息最近才出现，因此组织得不是很好。在本研究中，我们将回顾其中的一些问题以及当前采用或提出的克服这些问题的方法，并将化学和生物学发现转化为安全有效的孤儿病治疗方法。
