Parisi Daniele, Adasme Melissa F, Sveshnikova Anastasia, Bolz Sarah Naomi, Moreau Yves, Schroeder Michael
ESAT-STADIUS, KU Leuven, B-3001 Heverlee, Belgium.
Biotechnology Center (BIOTEC), Technische Universität Dresden, 01307 Dresden, Germany.
Comput Struct Biotechnol J. 2020 Apr 13;18:1043-1055. doi: 10.1016/j.csbj.2020.04.004. eCollection 2020.
Drug repositioning aims to find new indications for existing drugs in order to reduce drug development cost and time. Currently,there are numerous stories of successful drug repositioning that have been reported and many repurposed drugs are already available on the market. Although drug repositioning is often a product of serendipity, repositioning opportunities can be uncovered systematically. There are three systematic approaches to drug repositioning: disease-centric approach, target-centric and drug-centric. Disease-centric approaches identify close relationships between an old and a new indication. A target-centric approach links a known target and its established drug to a new indication. Lastly, a drug-centric approach connects a known drug to a new target and its associated indication. These three approaches differ in their potential and their limitations, but above all else, in the required start information and computing power. This raises the question of which approach prevails in current drug discovery and what that implies for future developments. To address this question, we systematically evaluated over 100 drugs, 200 target structures and over 300 indications from the Drug Repositioning Database. Each analyzed case was classified as one of the three repositioning approaches. For the majority of cases (more than 60%) the disease-centric definition was assigned. Almost 30% of the cases were classified as target-centric and less than 10% as drug-centric approaches. We concluded that, despite the use of umbrella term "drug" repositioning, disease- and target-centric approaches have dominated the field until now. We propose the use of drug-centric approaches while discussing reasons, such as structure-based repositioning techniques, to exploit the full potential of drug-target-disease connections.
药物重新定位旨在为现有药物寻找新的适应症，以降低药物开发成本和时间。目前，已有许多成功的药物重新定位案例被报道，并且许多重新利用的药物已在市场上有售。尽管药物重新定位通常是偶然发现的结果，但重新定位的机会也可以通过系统的方法来发现。药物重新定位有三种系统方法：以疾病为中心的方法、以靶点为中心的方法和以药物为中心的方法。以疾病为中心的方法确定新旧适应症之间的密切关系。以靶点为中心的方法将已知靶点及其已确定的药物与新适应症联系起来。最后，以药物为中心的方法将已知药物与新靶点及其相关适应症联系起来。这三种方法在潜力和局限性方面有所不同，但最重要的是，在所需的起始信息和计算能力方面有所不同。这就提出了一个问题，即哪种方法在当前的药物发现中占主导地位，以及这对未来的发展意味着什么。为了解决这个问题，我们系统地评估了药物重新定位数据库中的100多种药物、200种靶点结构和300多种适应症。每个分析的案例都被归类为三种重新定位方法之一。在大多数案例（超过60%）中，采用了以疾病为中心的定义。近30%的案例被归类为以靶点为中心，不到10%的案例被归类为以药物为中心的方法。我们得出结论认为，尽管使用了“药物”重新定位这个统称，但到目前为止，以疾病和靶点为中心的方法在该领域占据主导地位。我们建议在讨论基于结构的重新定位技术等原因时使用以药物为中心的方法，以充分利用药物-靶点-疾病之间的联系。
