Drug design

 electronic databases  contain molecules which have been isolated or synthesized and tested by pharmaceutical companies for possible pharmaceutical properties  information on compound:  name, structure, 3D image, properties, biological activity, …  pharmaceutical companies use such libraries to identify ‘lead’ compound for a particular ‘target’ molecule such as an enzyme, DNA or a receptor.

 involves simultaneous chemical synthesis  a large number of different but structurally related compounds (all possible combinations) from a small number of reactant molecules which are reacted with a variety of reactants,  uses “mix-and-split” technique and resin beads  screen each product for its biological activity, resulting in a “combinatorial library”.  all is automated and uses computers/robots

 A technique used in combinatorial chemistry  synthesizes large volume of compounds  reactions take place on the surface of resin beads  each type of reactant molecule is bonded covalently onto a very small resin bead  uses mix and split process

 When synthesis reactions are complete, the products are removed easily from the beads by filtering off the beads and washing them. After that the products are tested “in vitro” and “in vivo” to find out their biological activity.  Web: Mettler Toledo Mettler Toledo

 Parallel chemistry or parallel synthesis involves the synthesis of a smaller but selected group of compounds with a different compound in each reaction vessels. In most combinatorial techniques the compounds are mixed and need to be separated; not necessary in parallel synthesis as multiple experiments run in parallel.  Examples of companies:  ChemPartner: A Shanghai which specilializes in parallel synthesis ChemPartner: A Shanghai which specilializes in parallel synthesis  Mettler Toledo Mettler Toledo

Combinatorial synthesisParallel synthesis Generates large, more diverse libraries - “combinatorial library”. Produces a ‘mixture’ of compounds in same reaction vessel. Small focused libraries Reactions performed in different reaction vessels Produces a ‘single’ product in each reaction vessel.

 The different reactants are mixed and then split into separate portions i.e. each portion has all reactants  To each portion a different reactant is added and a reaction is allowed to occur  The separate portions are then mixed again after which they are split into separate portion  To each portion a different reactant is added again…  This is repeated.

 making/using combinatorial libraries  3D modeling software can be used to show interaction between medicine and active site on target molecule/receptor without actually making the medicine. This also allows the design of molecules with the perfect fit and then attempt to chemically produce them. Example:

 evaluation of (biological/pharmaceutical) effects of new drugs; if the structure of a new molecule is known or …  If the structure is changed a 3D model can be made and used to test its effectiveness in binding onto a target molecule

 many medicines are either non-polar or relatively non-polar molecules.  If their target area in the body is in an aqueous environment their low solubility in water, as a result of their non-polarity, will make their uptake slow  it will take time for the medicine, after administration, to reach its target molecule.

 In the case of non-polar molecules with either acidic (carboxylic acid) or basic (amine) groups the polarity can be increased by converting them into ionic salts by adding either alkalis or acids.  The ionic salt forms ionic/polar bonds with water  Examples: aspirin (acid) and fluoxetine (amine)

 Aspirin was derived from 2-hydroxybenzoic acid by esterification, next step…  Aspirin which is insoluble in water and which has a carboxylic acid group can be made into an ionic salt by reacting it with a strong alkali such sodium hydroxide to form a soluble sodium salt as shown by the equation below: C 6 H 4 (OCOCH 3 )COOH + NaOH → C 6 H 4 (OCOCH 3 )COONa + H 2 O

 Once in the stomach the conjugate base in the aspirin reacts with the H + in the stomach acid to reform the acidic aspirin molecule. C 6 H 4 (OCOCH 3 )COO - + H + → C 6 H 4 (OCOCH 3 )COOH

 fluoxetine hydrochloride (Prozac®), an ionic salt, is produced by reacting a strong acid such as hydrochloric acid with the secondary amine group in fluoxetine.  the nitrogen atom in the secondary amine donates its non-bonding pair to the hydrogen ion forming a basic cation to which the chloride ion is attracted.  F 3 C(C 6 H 4 )OCH(C 6 H 5 )CH 2 CH 2 NHCH 3 + HCl → F 3 C(C 6 H 4 )OCH(C 6 H 5 )CH 2 CH 2 N + H 2 CH 3 Cl -

 If enantiomers in a racemate have different physiological activities it is necessary to isolate the desired enantiomer from the mixture.  However, this is a wasteful process and it is therefore better to synthesize directly the desired enantiomer by preventing the synthesis of the other enantiomer. This can be achieved by using a chiral auxiliary.

 a chiral auxiliary is an enantiomer itself  used to convert a non-chiral reacting molecule into just one enantiomer i.e. the enantiomer with the desired pharmaceutical effect.  it does that by attaching itself to the non-chiral molecule to create the stereochemical conditions necessary to force the reaction to follow a certain path i.e. the production of the desired enantiomer and not the other enantiomer.  once the new desired molecule has been formed, the auxiliary can be taken off and recycled.