Practical aspects of NMR-based fragment screening

Abstract

NMR spectroscopy is a popular and highly versatile screening method for fragment-based drug discovery. NMR methods are capable of robustly detecting the binding of fragments to macromolecular targets over an extraordinarily broad affinity range (from covalent to millimolar). This chapter provides a stepwise process for creating an NMR-based fragment screening program. The construction of fragment libraries is described, including compound selection, plating of stocks, and preparation of mixtures. Guidance is given for designing fragment screens, such as choosing the appropriate NMR screening format and method, and optimizing the sample conditions and experimental parameters. The identification and validation of screening hits is described, and a number of potential pitfalls are discussed. Rather than detailing one specific screening protocol, this chapter outlines the available options and provides information to enable users to design their own customized fragment screening programs.