D9 Drug design Compound libraries Combinatorial and parallel chemistry The use of computers Modifications for polarity Chiral 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 design A chemical library or compound library - a collection of stored chemicals Used for scientific experimentation or industrial manufacture For each chemical there is information stored such as the chemical structure and physiochemical characteristics (melting point, polarity, reactivity)

Combinatorial and parallel chemistry Used 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 synthesis For eg protein synthesis The starting amino acid is covalently bound to very small beads of polystyren Amino acids are the coupled to the first one by a process known as mix and split For 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 washing Has been extended tp other types of molecules, eg benzodiazepines Once a particular substance has been identified it can be synthesized in a lager scale

D9.2 Explain the use of combinatorial and parallel chemistry to synthesize new drugs 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 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 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

How to modify the polarity of a molecule to increase its aqueous solubility ? Acidic (carboxylic acid) groups have the ability to form ionic salts Aspirin + NaOH Hydrogen bonding- relatively weak Moderately water soluble Ionic bonding relatively 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, unpolar Not 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 catalyst Separate 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

Synthesis with chiral auxilary (the molecule in blue) ee-enantiomeric excess

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