Combitorial chemistry

From DrugPedia: A Wikipedia for Drug discovery

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The main goal of Combinatorial Chemistry is to generate a large number of molecules, compounds that can be used in drug discovery process as potential drug molecules as quickly as possible.

Literal meaning of "Combinatorial" is "of", "related to", or "involving combinations". Combinatorial chemistry plays important role in Lead Discovery and Lead Optimization.

[edit] Various methods for Chemical systhesis

1. Solid-phase systhesis
2. Parallel(arrey) Solution-phase synthesis
3. Dipeptide systhesis

Solid-phase systhesis

In chemistry, solid-phase synthesis is a method in which molecules are bound on a bead and synthesized step-by-step in a reactant solution; compared [with] normal synthesis in a liquid state, it is easier to remove excess reactant or byproduct from the product. In this method, building blocks are protected at all reactive functional groups. The two functional groups that are able to participate in the desired reaction between building blocks in the solution and on the bead can be controlled by the order of deprotection. This method is used for the synthesis of peptides, deoxyribonucleic acid (DNA), and other molecules that need to be synthesized in a certain alignment. Recently, this method has also been used in combinatorial chemistry.

In the basic method of solid-phase synthesis, building blocks that have two function groups are used. One of the functional groups of the building block is usually protected by a protective group. The starting material is a bead which binds to the building block. At first, this bead is added into the solution of the protected building block and stirred. After the reaction between the bead and the protected building block is completed, the solution is removed and the bead is washed. Then the protecting group is removed and the above steps are repeated. After all steps are finished, the synthesized compound is cut off from the bead.

If a compound containing more than two kinds of building blocks is synthesized, a step is added before the deprotection of the building block bound to the bead; a functional group which is on the bead and did not react with an added building block has to be protected by another protecting group which is not removed at the deprotective condition of the building block. Byproducts which lack the building block of this step only are prevented by this step. In addition, this step makes it easy to purify the synthesized compound after cleavage from the bead.

Solid-phase synthesis of peptides

Solid-phase synthesis is the most common method for peptide synthesis. Usually, peptides are synthesized from the carbonyl group side to amino group side of the amino acid chain in this method, although peptides are synthesised in the opposite direction in cells. In peptide synthesis, an amino-protected amino acid is bound to a bead (a resin), forming a covalent bond between the carbonyl group and the resin. Then the amino group is deprotected and reacted with the carbonyl group of the next amino-protected amino acid.The bead now bears two amino acids. This cycle is repeated to form the desired peptide chain. After all reactions are complete, the synthesised peptide is cleaved from the bead.

Solid-phase synthesis of DNA

DNA is also synthesized by the solid-phase method. Although DNA can be synthesized in a flask, it is almost always synthesized by a DNA synthesizer in chemistry. The mechanism of DNA synthesis in a DNA synthesizer is based on solid-phase synthesis; it also uses a bead for synthesis.

Advantages of Solid-phase Synthesis

• Handling of material is easy and can be automated
• Purification is easy ; Simple washing and Filteration is usually all that is needed.

Disadvantages of solid-phase synthesis

• Quantites produced can be very low for very large liberaries (may be as low as 10s of nanomoles).
• Solution-phase methods don't always work applied to the solid-phase
• Charterization of intermediates is difficult, we cannot say with surity that our reaction has worked.

Parallel(arrey) Solution-phase Synthesis