D9 presentation

D.9 Drug Design

By: Sam, Rob, and

Farah

1

D.9 Drug Design

By: Sam, Rob, and

Farah

1

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

• A compound library is a collection of stored chemicals, typically used in drug discovery high-throughput screening and industrial manufacturing.

• Each chemical has all of its chemical information like its chemical structure, chemical properties, and physical properties, stored in a database.

• If a pharmaceutical chemist is in need of a chemical to perform a particular function, he or she can search the electronic compound library database.

• This eliminates the synthesizing and the individual evaluation in the laboratory of a large number of related compounds. Large numbers of related compounds can be created quickly.

• This approach saves money and time.

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

• Combinatorial Chemistry• Combinatorial chemistry involves the rapid synthesis

or computer simulation of a large number of different but structurally related molecules or materials.

• Used to synthesize a large number of different compounds.

• Produces an electronic database or combinatorial library.

• Used to mass produce drugs by two solid-phase synthesis.


Solid-Phase Synthesis• Starting material is covalently bonded to small polystyrene

beads• The beads are reacted with one another and then split and

reacted with new substances to make new combination of molecules

• Produced a wide range of molecules• The products are then purified by filtering of the beads and

washing• Used to build proteins (polypeptides)• This method is fully automated and uses robotics

• Sets of individual compounds are then prepared simultaneously by reacting with a number of different reagents in arrays of physically separate reaction vessels or micro-compartments w/o interchange of intermediates during the assembly process

• This allows a smaller, more focused library than that obtained with comb. chemistry

• First step towards producing larger yields of materials identified from screening tests

• They can then be fully characterized w/o need for huge and laborious identification procedures



Parallel Synthesis• Used to produce smaller, more focused compound

libraries• An alternative technique to complement combinatorial

chemistry• Still uses solid-phase chemistry but on a larger scale

than comb. chemistry• Advantage: all intermediates and products are generated

separately• Involves a synthesis of a highly reactive intermediates

D.9.3 Describe how computers are used in Drug Design

• It would be impossible to test millions of molecules in a lab against any given target, but the computerized screening process helps in designating a small set of molecules that can then be tested in a wet lab.

• “In-Silico Drug Design” is a series of methods in which the computer assists in the identification and development of medicine and drugs. There are several methods, each with a different purpose/ application

Molecular Docking and Virtual Screening: the ability to predict binding conformations and affinities of millions of molecules without the need of a single synthetic step

Molecular Dynamics: the prediction of the evolution of molecular systems over time, the study of protein conformation, protein-protein interactions, the simulation of biological membranes.

Quantum Mechanics: the study of chemical reactions, the effects of substitutions on electronic properties and reactivity of molecules

QSAR: Quantitative structure-activity relationship. The ability of predicting biological properties of molecules without even the need of knowing their target

Homology Modeling: predicting the structures of proteins that has not been yet crystallized

They include:


• One example is the CSIR Bio-Suite• The Indian CSIR

(Council for Scientific and Industrial Research) developed the “Bio-Suite” • a software tool to aid

in the drug discovery process.


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

• Most medicines/drugs are fairly complex organic molecules with low polarity. • Tend to be insoluble in water and other polar

environments in the body, which greatly limits their capacity as a medicine.

• To increase solubility, they can be administered as an ionic salt.

• If the molecule contains amines, then they can be converted into their hydrochloride acid

• This can be seen in the reaction of ammonia and hydrochloric acid.


• An example of such a drug is Fluoxetine Hydrochloride, more commonly known as Prozac

• The opiates contain an amine group and can therefore be administered as their hydrochloride salt.


• Another example is Diamorphine (Heroine)

• The white powder is actually Diacetylmorphine hydrochloride, making it soluble and possible to inject into the body.


• The same concept applies to drugs that contain a carboxylic acid group. These drugs can be made polar by converting them into their anion and administering them as a sodium or calcium salt.

• Take soluble aspirin for example. The anion of aspirin enters the body and returns to its unionized form once it has reached a strong acidic part of the body (the stomach)


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

• Traditionally, the synthesis of an optically active compound normally produces a racemic mixture of the two enantiomers. The mixture has to be separated into the two isomers.

• Recently, a technique using chiral auxiliaries has made it possible to synthesize just the desired isomer.

• A chiral auxiliary is an optically active chemical compound or unit that is temporarily incorporated into organic synthesis so that it can be carried out asymmetrically with the selective formation of one of two enantiomers.

• This is useful as enantiomers have identical chemical properties in relation to non-chiral reagents and cannot therefore be easily chemically separated.

• However, because of the different properties of enantiomers in biochemical reactions, separation is vital.


• The chiral auxiliary attaches 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 (recycled) to leave the desired enantiomer.


• Taxol is an anti-cancer drug that is synthesized using chiral auxiliaries.

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D9 presentation