Guixian Zhao, Mengping Zhu, Yangfeng Li, Gong Zhang, Yizhou Li
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引用次数: 0
摘要
导言:基于片段的药物设计(FBDD)针对具有挑战性的治疗靶点的有效性一直受到两个因素的阻碍:小规模的文库和片段到靶点优化过程的复杂性。DNA编码文库(DEL)技术提供了一种引人注目且稳健的高通量选择方法,有可能解决这些局限性:在这篇综述中,作者提出了一种观点,即 DEL 技术与 FBDD 的概念完全匹配,可促进命中发现。他们首先从药物化学的角度分析了FBDD的技术局限性,并解释了为什么DEL可以为这些局限性提供潜在的解决方案。随后,他们详细阐述了 DEL 与 FBDD 的整合工作原理。此外,他们还介绍了一些案例研究,包括新药发现和全配体发现,特别是针对具有广泛药物靶点界面的挑战性治疗靶点:基于 DEL 的片段发现的未来可能会受到技术进步和应用范围的双重推动。从技术层面来看,扩大 DEL 的化学多样性对于片段药物发现的成功至关重要。从应用范围来看,基于 DEL 的片段发现有望解决一系列具有挑战性的靶点。
Using DNA-encoded libraries of fragments for hit discovery of challenging therapeutic targets.
Introduction: The effectiveness of Fragment-based drug design (FBDD) for targeting challenging therapeutic targets has been hindered by two factors: the small library size and the complexity of the fragment-to-hit optimization process. The DNA-encoded library (DEL) technology offers a compelling and robust high-throughput selection approach to potentially address these limitations.
Area covered: In this review, the authors propose the viewpoint that the DEL technology matches perfectly with the concept of FBDD to facilitate hit discovery. They begin by analyzing the technical limitations of FBDD from a medicinal chemistry perspective and explain why DEL may offer potential solutions to these limitations. Subsequently, they elaborate in detail on how the integration of DEL with FBDD works. In addition, they present case studies involving both de novo hit discovery and full ligand discovery, especially for challenging therapeutic targets harboring broad drug-target interfaces.
Expert opinion: The future of DEL-based fragment discovery may be promoted by both technical advances and application scopes. From the technical aspect, expanding the chemical diversity of DEL will be essential to achieve success in fragment-based drug discovery. From the application scope side, DEL-based fragment discovery holds promise for tackling a series of challenging targets.
期刊介绍:
Expert Opinion on Drug Discovery (ISSN 1746-0441 [print], 1746-045X [electronic]) is a MEDLINE-indexed, peer-reviewed, international journal publishing review articles on novel technologies involved in the drug discovery process, leading to new leads and reduced attrition rates. Each article is structured to incorporate the author’s own expert opinion on the scope for future development.
The Editors welcome:
Reviews covering chemoinformatics; bioinformatics; assay development; novel screening technologies; in vitro/in vivo models; structure-based drug design; systems biology
Drug Case Histories examining the steps involved in the preclinical and clinical development of a particular drug
The audience consists of scientists and managers in the healthcare and pharmaceutical industry, academic pharmaceutical scientists and other closely related professionals looking to enhance the success of their drug candidates through optimisation at the preclinical level.