Combinatorial chemical probes

As techniques for chemical analysis are used in continually smaller domains, experimental challenges for inherently insensitive methods such as NMR spectroscopy become increasingly severe. Among the various schemes to boost the intrinsic sensitivity of an NMR experiment, the development of small-volume RF probes has experienced a renaissance during the past decade. Commercial NMR probes now allow analyses of nanomole quantities in microliter volumes from natural product extracts and combinatorial chemical syntheses. Figure 7.3.1.9 illustrates the range of volumes that can be examined by NMR probes and accessories such as microsample tubes and inserts. With recently reported advances in sample preconcentration for microcoil NMR analysis [51], dilute microliter-volume samples can now be concentrated into nanoliter-volume... 

Combinatorial Synthesis of Alkaloid-like Compounds In Search of Chemical Probes of Protein-Protein Interactions... 

M., Khadem, S., Leek, D. M., Arya, P. (2006) Part 1. Modular approach to obtaining diverse tetrahydroquinoline-derived polycyclic skeletons for use in high-throughput generation of natural-product-hke chemical probes. Journal of Combinatorial Chemistry, 8, 715-734. 

If it is necessary to measure NMR spectra on large numbers of samples, e.g., from combinatorial chemical synthesis or from large biofluid studies, then flow-injection probes are now in general use. Samples can be made up in 96-well plates using a specialized robotic system the plate is then transferred to a second robotic system in which the contents of a well can be extracted and flowed into the NMR probe where the sample is stopped and any NMR experiments carried out. After measurement, the sample is then sent back to the same well, to a well in a different plate, or to waste as desired. 

SI Cho, W Zheng, A Tropsha. Rational combinatorial library design 2. Rational design of targeted combinatorial peptide libraries using chemical similarity probe and the inverse QSAR approaches. J Chem Inf Comput Sci 38 259-268, 1998. 

Advances in chemical synthesis have enabled considerable sophistication in the construction of diverse compound libraries to probe protein function [61, 62). However, few general techniques exist that can directly assess binding mechanisms and evaluate ligand afEnities in a multiplexed format. To realize the full potential of combinatorial chemistry in the drug discovery process, generic and efficient tools must be applied that combine mixture-based techniques to characterize protein-ligand interactions with the strengths of diversity-oriented chemical synthesis. 

The aliquots of the solution-state chemical synthesis samples were directly injected into a standard HPLC-NMR probe by using a robotic liquid handler. The NMR software was used to automatically find and suppress the intense NMR signals from any non-deuterated solvents used, typically using the WET sequence [5]. Unlike the characterisation of impurities in organic compounds (see the next section) or drug metabolites (see the appropriate chapter in this volume) where the proportions of the analytes can be very different, combinatorial chemistry samples tend to be all of similar quantity and this simplifies the analysis in that it is not usually necessary to worry overly about carry-over of material from sample to sample, nor it is necessary to readjust the NMR spectrometer receiver gain after every sample, thus saving considerable machine time. 

DNLM 1. Molecular Probes—chemical synthesis—Laboratory Manuals. 2. Protein Array Analysis-methods—Laboratory Manuals. 3. Combinatorial Chemistry Techniques—Laboratory Manuals. 4. Genomics—methods—Laboratory Manuals. QU 25 C517 2005] I. Zanders, Edward D. II. Series. QH431.C45197 2005 572.8 6—dc22... 

Cho, S.J., Zheng, W. andTropsha, A. Rational Combinatorial Library Design. 2. Rational Design of Targeted Combinatorial Peptide libraries using chemical similarity probe and inverse QSARapproaches. J. Chem. Inf. Comput. Sci., 1998,38,259-268. 

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