Drug design
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Drug design. medicines. compound libraries. 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, …

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Drug design

Drug design

medicines


Compound libraries

compound libraries

  • 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.


Compound libraries1

compound libraries

  • From IB syllabus:

    • Traditionally, a large collection of related compounds are synthesized individually and evaluated for biological properties. This approach is time-consuming and expensive.


Combinatorial chemistry

combinatorial chemistry

  • involves simultaneous chemical synthesis

  • 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


Solid phase chemistry

solid-phase chemistry

  • 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


Mix and split

Mix and split

  • 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.


Advantage of solid phase

advantage of solid-phase

  • 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.


Parallel chemistry

parallel chemistry

  • 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.


Parallel synthesis

Parallel synthesis


Parallel synthesis1

Parallel synthesis


Similarities

Similarities


Differences

differences


Synthesis of new drugs

Synthesis of New Drugs

  • IB Syllabus says:

    • Combinatorial chemistry is used to synthesize a large number of different compounds and screen them for biological activity, resulting in a “combinatorial library”. Alternatively, parallel synthesis can produce smaller, more focused libraries. Students should be aware of the importance of solid-phase chemistry.


Use of computers in drug design

use of computers in drug design

  • Used in development and evaluation of drugs

  • 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.


Use of computers in drug design1

Use of computers in drug design

  • 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


Solubility and uptake

solubility and uptake

  • 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.


Improving solubility

improving solubility

  • 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.

  • Examples: aspirin (acid) and fluoxetine (amine)


Aspirin

aspirin

  • 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:

    C6H4(OCOCH3)COOH + NaOH → C6H4(OCOCH3)COONa + H2O


Aspirin1

aspirin

C6H4(OCOCH3)COOH + NaOH → C6H4(OCOCH3)COONa + H2O


Fluoxetine

fluoxetine

  • 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.


Fluoxetine to fluoxetine hydrochloride

Fluoxetine to fluoxetine hydrochloride


Chiral auxuliary

chiralauxuliary

  • 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.


Chiral auxiliary

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.


Chiral auxiliary1

Chiral auxiliary


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