Design of small molecule libraries for NMR screening and other applications in drug discovery

There are conceptual differences between high-throughput screening (HTS) and fragment-based screening by NMR. The number of compounds in libraries for NMR screening may be significantly smaller than those used for HTS. Because one relies on a small library its design is significantly important and is the object of this article. A short introduction on fragment-based NMR screening approaches will be provided. Although there are currently very few reports describing the design of libraries of small molecules for NMR screening, aspects of the question of how to compile diverse collections of small molecular fragments useful for drug design were previously addressed for the purposes of combinatorial library design and de novo drug design. As these disciplines are highly interrelated and are applied in an interconnected manner with NMR screening within the drug discovery process, a review of combinatorial library design and especially the building block or fragment selection strategies applied for combinatorial library design and de novo design is well suited to reveal fundamental strategies and potential techniques for the design of NMR screening libraries. This section will be rounded off by a report on hands-on-experience with the design of the Novartis second-site NMR screening library and practical considerations for the design of compound mixtures. Rather than providing an exact protocol general guidelines will be indicated.