Ligands from Combinatorial Libraries

ALIS reports only compounds that bind directly to the target of interest, preventing false positives that arise from off-target activity or interactions with substrates or other reagents. Since ALIS directly identifies bound components by MS, the incidence of false positives based on bulk effects and non-specific binding is lower than that of biochemical assays that yield a secondary readout of activity. 

As an example, the bifimctional epoxy ester core (+)-2 was reacted with building blocks 3-18 to yield solution-phase library NGL127A443 containing nominally 512 substitutionally and stereochemically unique compounds (Figs. 3.3, 3.4). Of these, 82% have a molecular weight unique to 0.050 amu. This library was combined with four other 500-member libraries to form a 2500-member primary library that was screened against the important antibacterial target dihydrofolate reductase (DHFR, also known as Fol-A). 

This screening experiment yielded the monochlorinated DHFR ligand 1 at m/z 515.24, corresponding to an [M+H]+ ion with a monoisotopic molecular weight of 514.23 amu. No signal for this ion was evident in an ALIS control experiment with DHFR in the absence of the screening library (Fig. 3.5). Table 3.1 shows a 

Affinity Selection -Mass Spectrometry System for the Discovery and Characterization 

The discovery of DHFR inhibitor NGD-157 demonstrates that ALIS is an efficient system for identifying novel, bioactive lead compounds from large combinatorial libraries. A single ALIS experiment containing over 2500 compounds is complete in under 10 min, allowing more than 250 000 compounds to 

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JA Loo, DE De-John, RRO Loo, PC Andrews. Application of mass spectrometry for characterizing and identifying ligands from combinatorial libraries. Ann Rep Medic Chem 31 319-325, 1996. 

Fig. 1.3 Various small-molecule peptoid ligands derived from combinatorial libraries...

Y. M. Dunayevskiy, J.-J. Lai, C. Quinn, F. Talley, P. Vouros Mass spectrometric identification of ligands selected from combinatorial libraries using gel filtration. Rapid Commun. Mass Spectrom. 1997, 11, 1178-1184. 

The combinatorial method relies on the selection of ligands from a library of S)mthetic ligands s)mthesized randomly. 

Halkes KM, St Hilaire PM, Crocker PR, Meldal M, Glycopeptides as oligosaccharide mimics high affinity sialopeptide ligands for sialoadhesin from combinatorial libraries, J. Comb. Chem., 5(1) 18-27, 2003. 

Peptidomimetic ligands for opioid receptors have also been identified from combinatorial libraries. Screening of an N-(substi-tuted)glycine peptoid library for affinity for ix opioid receptors yielded novel structures (251) with high affinity for these receptors (K = 6-46 nM) (953). A library of dipeptide amides with alkyl substituents on both the interior and C-terminal amides were prepared, and high affinity agonists for all three opioid receptors identified from the library (see Ref 946). Peptide libraries can also be further modified ["libraries from libraries" (954)] to yield new potential ligands for receptors. Thus an acety-... 

Dunayevskiy, Y.M. Lai, J-J. Quinn, C. Talley, F Vouros, P. Mass Spectrometric Identification of Ligands Selected from Combinatorial Libraries Using Gel Filtration, Rapid Commun. Mass Spectrom. 11, 1178-1184 (1997). 

To date, the most frequently used ligand for combinatorial approaches to catalyst development have been imine-type ligands. From a synthetic point of view this is logical, since imines are readily accessible from the reaction of aldehydes with primary or secondary amines. Since there are large numbers of aldehydes and amines that are commercially available the synthesis of a variety of imine ligands with different electronic and steric properties is easily achieved. Additionally, catalysts based on imine ligands are useful in a number of different catalytic processes. Libraries of imine ligands have been used in catalysts of the Strecker reaction, the aza-Diels-Alder reaction, diethylzinc addition, epoxidation, carbene insertions, and alkene polymerizations. 

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