D9 Drug design

1. D9 Drug design Daniel Brown

2. D9.1 Discuss the use of a compound libraryin drug design. • Traditionally, a large collection of related compounds are synthesized individually and evaluated for biological properties. However this is time consuming and expensive.

3. D9.1 Discuss the use of a compound libraryin drug design. • A chemical library or compound library is a collection of stored chemicals usually used ultimately in high-throughput screening (a method for scientific experimentation especially used in drug discovery and relevant to the fields of biology and chemistry)or industrial manufacture. The chemical library can consist in simple terms of a series of stored chemicals. Each chemical has associated information stored in some kind of database with information such as the chemical structure, purity, quantity, and physiochemical characteristics of the compound.

4. D9.2 Explain the use of combinatorial andparallel chemistry to synthesize newdrugs. • Combinatorial chemistry is used to synthesize a large number of different compounds and screen them for biological activity, resulting in a “combinatorial library”. Combinatorial chemistry involves the rapid synthesis or the computer simulation of a large number of different but structurally related molecules or materials.

5. D9.2 Explain the use of combinatorial andparallel chemistry to synthesize newdrugs. • Combinatorial chemistry has probably had its biggest impact in the pharmaceutical industry. Researchers attempting to optimize the activity profile of a compound create a 'library' of many different but related compounds.

6. D9.2 Explain the use of combinatorial andparallel chemistry to synthesize newdrugs. • Parallel synthesis can produce smaller, more focused libraries. ‘parallel synthesis’ has certain advantages over combinatorial chemistry in that all intermediates and products are generated separately and in sufficient amounts for full characterization and biological screening, without the need for long identification procedures.

7. D9.3 Describe how computers are used indrug design. • Three-dimensional models of drugs can be created using computer simulation and molecular modeling software can be used for the virtual development and evaluation of new drugs. • Useful in combinatorial chemistry.

8. D9.4 Discuss how the polarity of a molecule can be modified to increase its aqueous solubility and how this facilitates its distribution around the body. • Acidic (carboxylic acid) and basic (amine) groups have the ability to form ionic salts. • For example, soluble aspirin and fluoxetinehydrochloride (Prozac®).

9. D9.5 Describe the use of chiral auxiliaries toform the desired enantiomer. • A chiral auxiliary is used to convert a non-chiral molecule into just the desired enantiomer, thus avoiding the need to separate enantiomers from a mixture. It works by attaching itself to the non-chiral molecule to create the stereochemical conditions necessary to force the reaction to follow a certain path. Once the new molecule has been formed, the auxiliary can be taken off (recycled) to leave the desired enantiomer. • An example is the synthesis of Taxol, an anti-cancer drug.

10. Taxol (Paclitaxel)

11. D9.5 Describe the use of chiral auxiliaries toform the desired enantiomer. • A chiral auxiliary is a chemical compound or unit that is temporarily incorporated into an organic synthesis so that it can be carried out asymmetrically with the selective formation of one of two enantiomers.