Lead Discovery by NMR

Schade M (2007) Fragment-based lead discovery by NMR. Front Drag Des Discov 3 105-119... 

Keywords NMR, drug discovery, fragment based drug discovery, SAR by NMR, SAR by ILOEs, hit to lead... 

Among several other techniques, NMR spectroscopy has high potential to support the drug discovery process. NMR can be used both in lead finding and lead optimization, by addressing the following questions ... 

Unexpected results can lead to new opportunities, but the provenance of the discovery is not always clear from research publications. Bunnett [21 ] admitted that the discovery of the S RN1 mechanism (Scheme 2.9) was serendipitous, and the discoveries of hydroboration [4] and of the conservation of orbital symmetry in concerted reactions (Woodward was working on the synthesis of vitamin B12) [29] originated in unexpected results. In another context, monitoring by NMR of reaction products as they were formed led to the chance observation of negative signals (emission of radiation instead of the usual absorption), explained by CIDNP in radical pairs (Scheme 2.6 earlier see also Chapter 10) [30]. However, as Pasteur remarked in the nineteenth century [31], chance favours only the prepared mind . 

Fragments should be composed of drug-like chemical matter because substantial parts of a fragment hit will end up in the final lead candidate for in vivo assays. Therefore, we selected our NMR screening library from commercially available compound repositories that have a proven track record in lead discovery (e.g. by many years of use in HTS) and also as they include structures and substructures that occur in known marketed drugs, as well as in clinical and preclinical candidates. This ensures that the fragment library is built on several decades of experience in drug discovery. 

To give an overview of the breadth of applications of NMR, Fig. 12.1 summarizes the drug development process and indicates the role of NMR at various stages. Drug development is an iterative process and can be simplified by representing it with two interconnected cycles of activity. Cycle A involves the design or discovery of an initial lead followed by its synthesis and bioassay. Based on the initial assay results there may be several loops around this... 

The resonance study (6 ) of B10H12I2 establishes that the I atoms are substituted on the two B s giving B peaks at highest field. It is important that in this and the following B resonance studies of substituted boron hydrides, the positions of boron resonances are but little shifted from their relative positions in the pure hydrides. This discovery has made the field of substituted boron hydrides easily studied by NMR techniques, and should lead to the identification of presently unassigned resonance peaks in the pure hydrides themselves and provide a basis for studies of internal exchange reactions. Thus, we can expect more detailed analyses of the charge distributions in both the hydrides and their substitution products to appear in the near future. 

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