Resonator-based methods technology

Recently, the use of pulsed-field gradient (PFG) technology to obtain diffusion coefficients of molecules has been demonstrated as a useful technique for mixture analysis (53). Unlike any other 2D experiment, size-resolved or diffusion-resolved NMR assigns the resonances based on the diffusion coefficient for each proton (or other spin) in the molecule and therefore can be used to distinguish resonances arising from different molecules (63-70) (Fig. 22). A method that involves the use of PFG and TOCSY, called diffusion-encoded spectroscopy (DECODES), simplifies mixture analysis by NMR (71). The combination of PFG and TOCSY decodes the spin systems, allowing individual components in complicated mixtures to be assigned. A typical DECODES spectrum obtained in this manner is shown in Fig. 23. The use of TOCSY aids the calculation of the diffusion coefficient and determination of molecular identity. 

The example also highlights that different affinity-based methods will be used at the different stages of the hit-to-lead process, which is very much determined by the required information content While the very sensitive NMR approach was used to identify weakly binding fragments, more potent compounds were assessed using the less-sensitive surface plasmon resonance (SPR) technology in order to drive the hit expansion process and to initiate and inform chemistry design. 

Nuclear magnetic resonance (NMR) measurements are usually considered to be slow processes, but recent advances in the design of flow-through NMR cells have allowed the method to be applied in combinatorial chemistry 97). These technological improvements were applied to the development of two NMR-based high-throughput ee assays for evaluating the products of enzyme- or transition metal-catalyzed reactions 98). 

It should be noted that the problem of transient noise pulses can in principle be circumvented by use of suitable playback technology. For example, in the case of gramophone disks the use of a laser-based reader should eliminate any mechanical resonance effects and thus reduce the artifact to a large click which can be restored using the methods of previous sections. Of course, this does not help in the many cases where the original source medium has been discarded after transcription using standard equipment to another medium such as magnetic tape ... 

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