For combinatorial libraries

With these massive amounts of data produced in HTS for combinatorial libraries, tools become necessary to make it possible to navigate through these data and to extract the necessary information, to search - as is said quite often -for a needle in a haystack. 

Zheng W, Hung ST, Saunders JT, Seibel GL. PICCOLO a tool for combinatorial library design via multicriterion optimization. Pac Symp Biocomput 2000 588-99. 

Armstrong, R.W., Combs, A.R, Tempest, P.A., Brown, S.D., Keating, T.A. (1996) Multiple-Component Condensation Strategies for Combinatorial Library Synthesis. Accounts of Chemical Research, 29, 123-131. 

When the diphenyloxazilidinone 306 was treated with HF in pyridine, the fluorinated amine 307 was produced efficiently. This method has been applied for the synthesis of optically active (.SVct-i fluorodi phenyl methyl )a Iky l-amines that can be used for combinatorial libraries (Equation 53) <2000TA2033>. 

It is important to note that the same ALIS hardware and software used for combinatorial library screening is applicable to characterizing protein-ligand interactions using the methods described below. 

Rose S, Stevens A. (2003) Computational design strategies for combinatorial libraries. Curr. Opin. Chem. Biol. 7 331-339. 

Koch MA, Breinbauer R, Waldmann H. (2003) Protein structure similarity as guiding principle for combinatorial library design. Biol. Chem. 384 1265-1272. 

Generate a trial solution to the underlying problem. For combinatorial library design, a random selection of a subset of building blocks is generated. 

Fang LL, Wan M, Pennacchio M, Pan JM. Evaluation of evaporative light-scattering detector for combinatorial library quantitation by reversed phase HPLC. Journal of Combinatorial Chemistry 2, 254-257, 2000. 

Solid phase attachment of histidine-containing peptides by anchoring the imidazole ring to trityl resins has been developed for combinatorial library preparation of diketopiperazines <99TL809>. Histidine, histamine, and urocanic acid are edl imidazole-containing molecules that have been attached to a trityl-type resin to allow their application to combinatorial chemistry <99TL2825>. 

Grabowski, ., Baringhaus, . -H., Schneider, G. (2008) Scaffold diversity of natural products inspiration for combinatorial library design. Nat Prod Rep 25, 892-904. 

Blaney, J., Martin, E. (1997) Computational approaches for combinatorial library design and molecular diversity analysis. Curr Opin Chem Biol 1, 54-59. 

Application of Free-Wilson Selectivity Analysis for Combinatorial Library Design... 

ProSAR a new methodology for combinatorial library design. J Chem Inf Model49, 603-614. 

CLEVER A General Design Tool for Combinatorial Libraries... 

The advent of microwave-assisted synthesis has allowed chemists to rapidly optimize reaction conditions for combinatorial library development17-19. But how can one efficiently produce libraries of compounds employing chemistry developed and optimized... 

We have optimized an eight-way MUX coupled to a TOFMS analyzer to carry out eight-channel parallel LC/UV/MS analysis of combinatorial libraries14 in the past 2 years. This system has not only provided the capacity needed for library analysis, but also enabled simultaneous evaluation of experimental parameters to expedite the method development process. In this chapter, we discuss the optimization of this system and present a high-throughput protocol for combinatorial library analysis. We also compare the eight-channel parallel LC/UV/MS system to a conventional single channel LC/UV/MS system in terms of performance and operation. 

Without backpressure regulation for each channel, it is necessary to minimize the flow rate fluctuation over time. The relative standard deviation (RSD%) in retention time variation among the eight channels over 1 month for compounds A and B was less than 2% and for C and D it was less than 1%. The RSD% for all channels over a 1-month period for compounds A to D was 3.2, 2.4,1.6, and 1.5%, respectively. Therefore, this system is well suited for combinatorial library analysis. The UV chromatograms from channel 5 from different days are shown as an example in Fig. 2A. The retention times of the four compounds (compounds A to D) from all eight channels during a 1-month period are shown in Fig. 2B. 

To develop a method for combinatorial library analysis, we first analyzed six to eight representative compounds from each library under generic LC/UV/MS conditions. These conditions would be used for library analysis unless adjustments had to be made based on the study of these representative compounds. 

Another use for combinatorial libraries has been the screening of peptides for antimicrobrial properties. In this case, the design of the library is based on antimicrobial peptides found in nature. A combinatorial synthesis is used to find alternative unnatural amino acids expected to mimic the antimicrobial properties.23 Peptide libraries also have been used to find compounds that could bind the lytic peptide mellitin.24 The library was synthesized in solution phase, purified, and evaluated using time-of-flight mass spectrometry (TOF-MS). The sequences determined to bind to mellitin contained hydrophobic pairs. By binding to mellitin, they were able to prevent the cell-surface mellitin interaction. This is an example of a peptide library able to afford compounds that interact with other small peptides without having to find an interacting protein first. 

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