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Solid phase synthesis for drug discovery ('parallel synthesis' vs 'split-pool' strategy)

Both for target-oriented synthesis and for diversity-oriented synthesis, solid phase synthesis is used in much the same way as oligonucleotides are. synthesized in gene synthesis machines (consult Chapter 8 for gene synthesis machines). In organic synthesis' of a protein, the nascent chains are immobilized. on polystyrene beads and building blocks (amino acids) are linked by the readily formed peptide bonds. The coupling reagents are added in high molar excess and the by-products are removed by washing the insoluble beads. The synthetic products are then purified from these by-products which would also include unused reagents.

Solid Phase synthesis in Parallel

Solid phase synthesis can be conducted in parallel, where in similar reactions, building blocks with varied structures are used in key fragment-coupling steps This parallel synthesis is an example of what is commonly also referred to as combinatorial synthesis, and utilized by medical chemists both in pharmaceutical industry and academia to synthesize a focussed library of related compounds, sharing structural features that are necessary for binding to a preselected protein target in the cell.

Parallel Synthesis

Parallel Synthesis and Split - Pool Strategy, used for the Synthesis of a Combinatorial Litrory for drug Discovery

Parallel Synthesis

Parallel Synthesis 2

Solid phase synthesis using 'split-pool' strategy.

In split-pool method, a collection of polystyrene beads used for solid phase synthesis as above, is split into many reaction vessels, and to each vessel, a unique set of reagents (one of the building blocks) is added. Cycles of pooling, resplitting, and further chemistry results in a large collection of compounds that are spatially segregated on unique beads. This is why, split-pool synthesis is also referred to as 'one bead-one compound' approach, and is analogous to genetic recombination, where each recombinant product is segregated in gametes.

Split pool Synthesis (few containers needed)

Parallel Synthesis and Split - Pool Strategy, used for the Synthesis of a Combinatorial Litrory for drug Discovery

Split pool synthesis (few containers needed)

Split pool synthesis (few containers needed) 2

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Diversity-Oriented Organic Synthesis and Evolving Synthetic Analysis Solid Phase Synthesis for Drug Discovery Combinatorial Biocatalysis for Drug Disovery Synthesis of Bergenin Derivatives Drug Discovery in Cancer Research Microbial Genomics for New Antibiotics Genomics Drugs (Pharmacogenomics) Immunotoxins as Drugs Drug Designing Drug Designing by Blocking Enzyme Activity Drug Designing through Blocking Hormone Receptors Drug Designing through Inhibition of Nucleic Acid Synthesis Drug Designing Against Heterogeneous Targets