Option D.9 – Drug Design

Option D.9 – Drug Design

D.9.1 – Discuss the use of a compound library in drug design

When drugs are designed, chemists do not start from scratch testing out new compounds at random – they take existing knowledge and build upon it.

A compound library is a collection of chemicals that are stored to be screened for a particular use, including biological activity in a certain area. The information about each of these chemicals is also kept on a database for later reference, such as its structure, characteristics, purity and the quantity that is stored.

If the need for a compound with certain properties is required, chemists can first search the database for chemicals that have similar properties. They can then go on to conduct further research on these drugs. This way, chemists do not waste time with the older methods of synthesising a range of related compounds, and then testing them individually. Using the compound library, they can immediately identify the chemicals with the properties they desire.

D.9.2 – Explain the use of combinatorial and parallel chemistry to synthesise new drugs

Combinatorial Chemistry

 

In this method, a large number of related chemicals are produced at once. A variety of starting materials are reacted in all possible combinations, aided by robotics. Chemists start with a drug that has known biological activity, which is called the lead compound. These reactions are able to take place simultaneously, and very rapidly.

These new chemicals will then be screened for biological activity to look for improvements, such as reduced side-effects, cheaper production or the ease of administering the drug.

Only one of these chemicals would be the active compound that would be used as the drug, but it is much faster and effective to produce it this way than to form it on its own. This is because all of the compounds are formed simultaneously.

Computer-control machines are used to perform repetitive tasks, as well as being able to produce compounds on a smaller scale. A specific reaction pathway is determined, and the different reagents are then mixed in separate vessels.

Solid-phase chemistry (mix-and-split) is when the reactions take place on porous, insoluble resin beads. The compound in built on the functional units, or linkers, of the beads. After each reactant is added, the beads are split into three groups to react with different substances. They will then be remixed and split again.

Once the reactions are complete, it will be cleaved from the bead using a certain reagent. This mix-and-split method is used to minimise the number of steps in the process, whilst also increasing the number of different compounds that can be produced. Any unreacted reagents can be easily washed away to reduce time.

Parallel Chemistry

In this method, the reactions all have a theme. The products are more focused and less diverse than in other methods, forming smaller compound libraries. The range of compounds formed is a subset of all the possible combinations. Each of the five products is tested to identify which is the active compound. This is more effective than producing a larger library; however, to do this, chemists must first have an idea of the types of functional groups that are necessary for the drug being manufactured.

This makes use of robotics to ensure the precision of the reactions and perform the tedious tasks. The difference here is that in each reaction flask, only a single product will form, instead of having multiple products mixed together like in combinatorial chemistry. This allows for each of the products to be tested separately.

Porous resins can also be used in this method, usually in the form of teabag procedures. The resins are suspended in the reagents inside bags

D.9.3 – Describe how computers are used in drug design

Computer programs are able to model the structure of molecules, and are able to systematically change the structure according to specific requirements. The process of three-dimensional computer modelling is also called “in-silico.” This software falls under the category of computer-aided design (CAD), allowing chemists to see whether the structure and shape of a certain drug are suitable for the receptor site, such as an enzyme. The activity of the drug can be evaluated without actually having to make it.

D.9.4 – Discuss how the polarity of a molecule can be modified to increase its aqueous solubility and how this facilitates its distribution around the body.

The solubility of a drug depends on its polarity. For it to dissolve well in aqueous solution, it needs to be more polar. Since the human body transports drugs in the blood, which contains water, chemists will try to improve the polarity of drugs.

One way of doing this is to create drugs that act as acids or bases, which will form soluble salts in solution. Such compounds may have carboxylic acid or amine groups, which form ions through the loss or gain of electrons. A common drug that applies this principle is aspirin, which is formed form acetylsalicyclic acid. It is reacted in an acid-base reaction to form a salt. The carboxylic acid group is essential here.

Another example is Prozac, or fluoxetine hydrochloride. The non-polar molecule fluoxetine gains a hydrogen on the amine and can bond with the negative chloride ion. This makes it soluble in the aqueous solutions of the body.

D.9.5 – Describe the use of chiral auxiliaries to form the desired enantiomers

Many compounds can form isomers, but usually only one enantiomer is active and useful as a drug. Although it is possible to isolate the desired enantiomer from a racemic mixture, it is very wasteful because some of the products will not be used.

Using a chiral auxiliary, chemists can produce a single enantiomer. The auxiliary molecule attaches to the reactant during the reaction to force the product to form with a certain structure. This process is also called asymmetric synthesis or enantioselective synthesis. By using chiral reagents, the other enantiomers will not be able to react. Once the desired product is formed, the auxiliary can be removed and reused.

For example, the anti-cancer drug Taxol® is synthesised using this method.