Fragment-Based Drug Discovery by NMR. Where Are the Successes and Where can It Be Improved?

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.

Automated summary

The definitions of pharmaceutical drug and drug discovery have changed significantly over the past century. Drug discovery now involves multiple stages aimed at obtaining molecules that can interact with specific biomolecular targets. High Throughput Screening (HTS) and Fragment Based Drug Design (FBDD) are commonly used approaches in the early stages of drug discovery. Nuclear Magnetic Resonance (NMR) spectroscopy is widely used in both industry and academia for FBDD. This manuscript discusses the role of NMR in the development of successful and unsuccessful molecules, focusing on the techniques used and evaluating the strengths and weaknesses of each stage through case studies.