The SHAPES strategy: an NMR-based approach for lead generation in drug discovery

Background: Recently, it has been shown that nuclear magnetic resonance (NM R) may be used to identify ligands that bind to low molecular weight protei n drug targets. Recognizing the utility of NMR as a very sensitive method f or detecting binding, we have focused on developing alternative approaches that are applicable to larger molecular weight drug targets and do not requ ire isotopic labeling. Results: A new method for lead generation (SHAPES) is described that uses N MR to detect binding of a limited but diverse library of small molecules to a potential drug target. The compound scaffolds are derived from shapes mo st commonly found in known therapeutic agents, NMR detection of low (mu M-m M) affinity binding is achieved using either differential line broadening o r transferred NOE (nuclear Overhauser effect) NMR techniques. Conclusions: The SHAPES method for lead generation by NMR is useful for ide ntifying potential lead classes of drugs early in a drug design program, an d is easily integrated with other discovery tools such as virtual screening , high-throughput screening and combinatorial chemistry.