NMR-based screening in drug discovery

Abstract

1. Introduction 2112. Screening methods 2132.1 Chemical shifts 2132.2 Diffusion 2142.3 Transverse relaxation 2182.4 Nuclear Overhauser effects 2183. Strategies for drug discovery and design 2213.1 Fragment-based methods 2213.1.1 Linked-fragment approach 2213.1.2 Directed combinatorial libraries 2223.1.3 Modification of high-affinity ligands 2233.1.4 Solvent mapping techniques 2233.2 High-throughput NMR-based screening 2243.3 Enzymatic assays 2264. Discovery of novel ligands 2274.1 High-affinity ligands for FKBP 2274.2 Potent inhibitors of stromelysin 2294.3 Ligands for the DNA-binding domain of the E2 protein 2334.4 Discovery of Erm methyltransferase inhibitors 2334.5 Phosphotyrosine mimetics for SH2 domains 2365. Conclusions 2376. References 237A critical step in the drug discovery process is the identification of high-affinity ligands for macromolecular targets. Traditionally, the identification of such lead compounds has been accomplished through the high-throughout screening (HTS) of corporate compound repositories. Conventional HTS methodology has enjoyed widespread application and success in the pharmaceutical industry and, through recent technological advances in screening (Fernandes, 1998; Oldenburg et al. 1998; Silverman et al. 1998) and combinatorial chemistry (Fauchere et al. 1998; Fecik et al. 1998), these programs will continue to have a prominent role in drug discovery. However, suitable leads cannot always be found using conventional methods. This is not surprising since typical corporate libraries contain fewer than 106 compounds compared with the estimated 1050–1080 universe of compounds (Martin, 1997). In addition, most conventional assays are limited to screening libraries of compounds against proteins with known function, excluding the large number of targets becoming available from genomics research.Recently, a number of NMR-based screening methods have been employed to identify and design lead ligands for protein targets (see Table 1). These NMR-based strategies can augment ongoing conventional HTS for identifying leads and can be used to aid in lead optimization. All of these techniques take advantage of the fact that upon complex formation between a target molecule and a ligand, significant perturbations can be observed in NMR-sensitive parameters of either the target or the ligand. These perturbations can be used qualitatively to detect ligand binding or quantitatively to assess the strength of the binding interaction. In addition, some of the techniques allow the identification of the ligand binding site or which part of the ligand is responsible for interacting with the target. In this article, the current state of NMR-based screening is reviewed.