基于结构的虚拟筛选技术能更广泛应用于现代药物发现?(英文)

Should structure-based virtual screening techniques be used more extensively in modern drug discovery?

总结了计算机辅助药物设计目前的状况,重点讨论了基于结构类的虚拟筛选方法,特别是分子对接方法。在药物发现过程中,这些方法除了在早期的从数据库到命中阶段可节省费用外,还能提供其他有用信息吗?本综述试图通过探究大量现有对接方法的优缺点来回答这一问题。结果表明:基于结构的药物设计还没有实现其早期的所有目标,还需要广泛深入地进行研究,应用时也需谨慎。令人兴奋的是当与其他互补的药物设计途径,如基于配体的方法,相结合时基于结构的方法是最好的。从这一点上看,基于结构的药物设计方法在现代药物发现这一多学科的交叉领域中还应该发挥更多的作用。

The drug discovery processes used by academic and industrial scientists are nowadays being questioned. The approaches of the pharmaceutical industry that were successful 20 years ago are simply not suitable anymore for the increasing complexity of available biological targets and the raising standards for medical safety. While the current scientific context resulting from significant developments in genomic, proteomic, organic synthesis and biochemistry seems particularly favorable, the efficiency of drug research does not appear to be following the trend. In particular, the in silico approaches, often considered as potential enhancements for classic drug discovery, are an interesting case. Techniques such as virtual screening did undergo many significant progresses in the past 5-10 years and have proven their usefulness in hit discovery approaches for who wants to avoid carrying out too many expensive experimental tests while exploring an important molecular diversity. However, reliability is still deceiving despite constant enhancements, and results are unpredictable. What are the origins of such issues？ In this short review, we will first summarize the current status of computer-aided drug design, then we will focus on the structure- based class of virtual screening approaches, for which docking programs constitute the main part. Can such methods give something more than cost savings in the early banks-to-hit phases of the drug discovery process？ We will try to answer this question by exploring the highlights and pitfalls of the great variety of docking approaches. It will appear that while the structure-based drug design field is not yet ready to fulfill all of its early promises, it should still be investigated extensively and used with caution. Most interestingly, structure-based methods are best used when combined with other complementary drug design approaches such as the ligand-based ones. In this regard, they will have an increasing role to play in modern drug discovery, which is more and more interdisciplinary.