Fragment-Based Drug Discovery by NMR. Where Are the Successes and Where can It Be Improved?
Fragment-Based Drug Discovery by NMR. Where Are the Successes and Where can It Be Improved?
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DOI：
10.3389/fmolb.2022.834453
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发表时间：
2022
影响因子：
5
通讯作者：
Vuister GW
中科院分区：
文献类型：
--
作者：
Mureddu LG;Vuister GW
在过去的世纪，药物和药物发现的定义发生了很大的变化。从几乎完全偶然的方法演变而来，如今的药物发现涉及几个不同的，但有时相互关联的阶段，旨在获得能够与定义的生物分子靶点相互作用的分子，并引发合适的生物反应。在每一个阶段，通常采用各种技术来获得将项目转入下一阶段所需的结果。高通量筛选（HTS）和基于片段的药物设计（FBDD）是用于在药物发现的早期阶段识别药物样候选物的两种主要方法。核磁共振（NMR）光谱在FBDD中有许多应用，并广泛用于工业和学术界。在这篇手稿中，我们讨论了成功和不成功的分子的路径，其中NMR在它们的发展中起着至关重要的作用。我们特别关注所使用的技术，并通过研究几个案例研究来描述每个阶段的优点和缺点。更准确地说，我们检查了AZD 3839与BACE-1相互作用、ABT-199与BCL 2/XL相互作用和S64315与MCL-1相互作用从初步筛选到最终先导化合物优化的开发历史。基于这些研究，我们得出的意见和结论，通过NMR的FBDD过程，并讨论其潜在的改进。
Over the last century, the definitions of pharmaceutical drug and drug discovery have changed considerably. Evolving from an almost exclusively serendipitous approach, drug discovery nowadays involves several distinct, yet sometimes interconnected stages aimed at obtaining molecules able to interact with a defined biomolecular target, and triggering a suitable biological response. At each of the stages, a wide range of techniques are typically employed to obtain the results required to move the project into the next stage. High Throughput Screening (HTS) and Fragment Based Drug Design (FBDD) are the two main approaches used to identify drug-like candidates in the early stages of drug discovery. Nuclear Magnetic Resonance (NMR) spectroscopy has many applications in FBDD and is used extensively in industry as well as in academia. In this manuscript, we discuss the paths of both successful and unsuccessful molecules where NMR had a crucial part in their development. We specifically focus on the techniques used and describe strengths and weaknesses of each stage by examining several case studies. More precisely, we examine the development history from the primary screening to the final lead optimisation of AZD3839 interacting with BACE-1, ABT-199 interacting with BCL2/XL and S64315 interacting with MCL-1. Based on these studies, we derive observations and conclusions regarding the FBDD process by NMR and discuss its potential improvements.
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