Combinatorial libraries methods

Park SI, Renil M, Vikstrom B et al (2002) The use of one-bead one-compound combinatorial library method to identify peptide ligands for cz4f31 integrin receptor in non-Hodgkin s lymphoma. Lett Pept Sci 8 171-178... 

L. English (Ed.), Combinatorial Library Methods and Protocols, Humana Press, Totowa, NJ, 2002. 

Moran, E. J. Sarshar, S. Cargill, J. F. Shahbaz, M. M. Lio, A. M. Mjalli, A. M. M. Armstrong, R. W. Radio Frequency Tag Encoded Combinatorial Library Method for the Discovery of Tripeptide-Substituted Cinnamic Acid Inhibitors of the Protein Tyrosine Phosphatase PTP1B, J. Am. Chem. Soc. 1995, 777,10787. 

In 1991, we first introduced the one-bead one-compound (OBOC ) combinatorial library method.1 Since then, it has been successfully applied to the identification of ligands for a large number of biological targets.2,3 Using well-established on-bead binding or functional assays, the OBOC method is highly efficient and practical. A random library of millions of beads can be rapidly screened in parallel for a specific acceptor molecule (receptor, antibody, enzyme, virus, etc.). The amount of acceptor needed is minute compared to solution phase assay in microtiter plates. The positive beads with active compounds are easily isolated and subjected to structural determination. For peptides that contain natural amino acids and have a free N-terminus, we routinely use an automatic protein sequencer with Edman chemistry, which converts each a-amino acid sequentially to its phenylthiohydantoin (PTH) derivatives, to determine the structure of peptide on the positive beads. 

We first reported the one-bead one-compound (OBOC) combinatorial library method in 1991.1 In this method, compound beads are prepared by a split-mix synthesis approach1 3 (Fig. 1) that results in the display of many copies of the same compound on one single bead.1,4 Tens of thousands to millions of these compound beads can easily be prepared. The bead library is then mixed with a target molecule, such as a protein, an... 

Lam, K. S. 1997. Application of combinatorial library methods in cancer research and drug discovery. Anticancer Drug Des.,12,145-167. 

Moran EJ, Sarshar S, Cargill JF, Shahbaz M, Lio A, Mjalli AMM, Armstrong RW, Radiofrequency tog encoded combinatorial library method for the discovery of tripeptide-substituted cinnamic acid inhibitors of the protein tyrosine phosphatase PTPSB J. Am. Chem. Soc., 117 10787-1788, 1995. 

Lam KS, Lebl M, Krchnak V, The one-bead one-compound combinatorial library method. Chem. Rev., 97 411-448, 1997. 

Lam KS, Lake D, Salmon SE, Smith J, Chen ML, Wade S, Abdul-Latif F, Leblova Z, Ferguson RD, Krchnak Y, Sepetov NF, Lebl M, A one-bead one-peptide combinatorial library method for B-cell epitope mapping, Methods Meth. Enzymol., 9 482 -93, 1996. 

Lam KS, Enzyme-linked colorimetric screening of a one-bead one-compound combinatorial library, Methods Mol. Biol., 87 7-12, 1998. 

Nielsen J, Janda KD, Toward chemical implementation of encoded combinatorial libraries, Methods Meth. Enzymol., 6 361-371, 1994. 

Table 1 Comparison of selected combinatorial library methods...

The OBOC combinatorial library method is highly versatile and economical. It also is a form of chemical microarrays. Many investigators successfully have applied the on-bead screening methods in their research. The solution-phase and cell-based assays for OBOC libraries, however, are much less developed and have been applied successfully in only a few laboratories. A need exists to develop robust methods that allow investigators to screen routinely huge OBOC releasable peptide or chemical libraries (e.g., 200,000 compounds) with multiparametric... 

Table 2 Combinatorial library methods and their applications...

EJ Moran, S Sarshar, JF Cargill, MM Shahbaz, A Lio, AMM Mjalli, RW Armstrong. Radio frequency tag encoded combinatorial library method for discovery of tri peptide-substituted cinnamic acid inhibitors of the protein tyrosine phosphatase PTP1B. J Am Chem Soc 117 10787-10788, 1995. 

---