D9 Drug designCompound librariesCombinatorial and parallel chemistryThe use of computersModifications for polarityChiral synthesis

How are drugs found?

Plants and fungi have healing properties, e.g. willow tree bark and poppy seeds

The active substance in the specimen

is purified and it’s structure analysed (salicylic acid

and morphine)A large collection of related compounds are synthesized

individually and evaluated for biological properties- time consuming and expensive (aspirin and heroin)

Substances can also be accidentally found (penicillin), the analogues are synthesized

The use of compound libraries in drug designA chemical library or compound library - a collection

of stored chemicals Used for scientific experimentation or industrial

manufactureFor each chemical there is information stored such

as the chemical structure and physiochemical characteristics (melting point, polarity, reactivity)

Combinatorial and parallel chemistryUsed to synthesize a large number of different

compounds and screen them for biological activity Result 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

Parallell chemistry

Solid-phase organic synthesisFor eg protein synthesisThe starting amino acid is covalently bound to very

small beads of polystyrenAmino acids are the coupled to the first one by a

process known as mix and

splitFor 3 aminoacids nine

possible dipeptides can

be formed, etc.

3 amino acids, X, Y and Z

By using large amounts of the second and subsequent Amino acids the reactions can be made with high yields

Solid-phase organic synthesis, cont.The resulting peptides can be easily purified by fi

ltering off the beads and washingHas been extended tp other types of molecules, eg

benzodiazepinesOnce a particular substance

has been identified it can be

synthesized in a lager scale

D9.2 Explain the use of combinatorial andparallel chemistry to synthesize newdrugsCombinatorial 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

Parallel synthesis can produce smaller, more focused libraries and 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.

The use of molecular modelling in drug designThree-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

How to modify the polarity of a molecule to increase its aqueous solubility ?Acidic (carboxylic acid) groups have the ability to

form ionic saltsAspirin

+ NaOH

Hydrogen bonding-relatively weakModerately water soluble

Ionic bondingrelatively strong-Water soluble

How to modify the polarity of a molecule to increase its aqueous solubility, cont.

Basic (amine) groups have the ability to form ionic salts

Fluoxetine hydrochloride (Prozac®).

+ HCl

Hydrogen bonding but mostly van der Waal – weak, unpolarNot water soluble

… turn it into a salt!

Drugs with carboxylic groups can be reacted with sodium (or potassium) hydroxide to be made into a salt

Drugs with amine groups can be reacted with hydrogen chloride to be made into a salt- a hydrochloride

Chiral synthesis- how to make the enantiomer you want and to avoid the other

Start with chiral molecule (eg glucose)Use chiral auxiliary*Chiral catalystSeparate the mixture on a chiral column

Definition of chiral auxiliary

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

The use of chiral auxiliaries

A chiral auxiliary is used in the synthesis to convert a non-chiral molecule into 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 to leave the desired enantiomer

ee-enantiomeric excess

Synthesis with chiral auxilary (the molecule in blue)

Chiral auxiliaries are used for the synthesis of Taxol, an anti-cancer drug

Taxol (Paclitaxel)