Combinatorial synthesis has following application: - Creating libraries of organic molecules for drug screening (finding candidate molecules

- Lead compounds, that interact with a given target receptor in the body) - Lead optimization (perfecting a potentially useful lead molecule). Essentially, the process involves taking a small number of starting compounds and reacting these with a larger number of reagents. For example, with 20 starting compounds and 50 reagents, 1000 products can be generated. These products can be reacted with a further collection of 50 reagents. The result would be 50,000 second generation products. Lead optimization: Lead optimization aims at enhancing the most promising compounds to improve effectiveness, diminish toxicity, or increase absorption. Many of the technologies for lead discovery overlap with lead optimization as researchers attempt to incorporate the best drug characteristics early in the process. Requirements for lead optimization: At the very beginning, one needs to evaluate risks before committing significant resources to the project such as: First, it must be verified that the target is viable as it is needed to accurately determine if an appropriate target is available. Second, the design of the screening library also is critical. It needs highquality libraries to eliminate reactive functional groups. This helps reduce false positives. Third, the assays must be time efficient. To achieve more success reassaying should be performed once a lead compound is obtained.


For lead optimization there are two major methods: Pool and split method: Involves attaching the starting compounds to polymer beads. The beads are then split into 50 groups and reacted with the second set of reagents. After this reaction, all the beads are pooled, mixed together, and split into 50 groups again. If mixing is efficient, each group should contain approximately equal numbers of beads representing each of the 1000 first-generation products. The groups of beads are then reacted with the next set of reagents. If the beads are tagged in some way after each reaction (for example, with a different fluorescent label to identify each reagent) the combination of tags will characterise each of the 50 000 second-generation products exactly. The

finished beads can be screened for their ability to bind a particular target protein in the body. The compound with the best performance can be identified and tested further. Additional rounds of pooling and splitting allow libraries with millions of compounds to be generated and subjected to highthroughput screening (HTS). Parallel synthesis: All the different chemical structure combinations are prepared separately, in parallel, using thousands of reaction vessels and a robot programmed to add the appropriate reagents to each one. This method is unsuitable for the creation of very diverse libraries but is very useful for the development of smaller and more specialised libraries based on a particular skeleton.

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