Once a target molecule has been identified for a particular drug, the next step is to find a lead compound - one that shows the desired pharmaceutical activity - which will be used as a start for the drug design and development process. In the past, this step involved the individual synthesis and testing of candidate molecules, which was an extremely slow and expensive process. The information derived from these syntheses and testing procedures led to the production of compound libraries, with details on the molecules' activities stored for possible future reference.
The increasing demand for more efficient ways of generating larger libraries of potential drug candidate molecule and screening these compounds for biologically relevant information has led to such major developments as combinatorial synthesis, parallel synthesis and high-throughput screening. While still relatively new approaches, they are widely used by all major pharmaceutical companies and it is hoped that this high-volume approach to the discovery of medicines will lead to an increase in the number of viable new products at an affordable cost.
D.9.2 Explain the use of combinatorial and parallel chemistry to synthesize new drugs
Combinatoral chemistry is a method for synthesizing groups of compounds known as combinatoral libraries simultaneously, rather than one by one as in the more traditional approach. Typical library sizes vary from 10000 to 500000 compounds.
By using specially designed machines that are largely automated, the synthesis reactions occur on a very small scale and generate a poll of chemically related compounds. The reactions take place in separate vessels, following a defined reaction route with a large variety of starting materials and reagents. Combinatoral chemistry in a sense mimics the natural process of random mutation and selection of the fittest - meaning in this case those with the best activity. Subsequent screening of the products for the desired activity will hopefully identify a useful lead compound.
A popular way of generating the different structures with the minimum number of steps is known as the mix and split method. Each of the three compounds is first linked to solid support (resin bead) and then the beads are mixed and split into three equal portions. Each portions is then reacted with a different building block, giving rise to dimers of which there will be nine possible structures.
A variation on this, known as parallel synthesis, carries out the reactions in such a way to produce a single product in each reaction flask. It generally produces libraries that are more focused and less diverse than those from combinatorial techniques.
Parallel synthesis usually involves the synthesis of a highly reactive intermediate via a series of simple steps, then its subsequent reactions with a number of different reagent.
Parallel rather than mixed syntheses are used in the research of structure-activity relationships and in drug optimizations, as these involve separate testing of each compound. Overall, the pharmaceutical industry is seeing an increase in multiple parallel syntheses, with a decline in mixed combinatorial syntheses.
D.9.3 Describe how computers are used in drug design
Computational chemistry has made huge strides in recent years, opening up a relatively new approach to drug design known as computer-aided design (CAD). Molecular-modelling software analyses the interaction between the drug and its receptor site, helping to design molecules that give an optimal fit. Progress in this field is largely possible due to increasing knowledge of the three-dimensional strcture of the biomolecular target obtained through methods such as X-ray crystallography and nuclear magnetic resonance (NMR) techniques.
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 drugs are transported in the blood. The term bioavailability is used to describe the percentage of a dose of a drug that reaches the bloodstream. Due to the fact that drugs may be misdirected or broken down before absorption, typically the figure is about 20%-40%. Once in the blood, drugs are transported in aqueous solution in the plasma. In general, drugs that are more polar or have ionic groups will dissolve more readily and hence be distributed to the target cells more efficiently. Some drugs can be modified to increase their solubility.
The structure of aspirin contains an ester group and a carboxylic group attached to a benzene ring. When it is reacted with a strong alkali, it forms a salt in which the carboxylic acid group is converted into its conjugate base, the acid anion. This increase the aqueous solubility of the compound; formulations containing the salt of the acid are known as soluble aspirin.
D.9.5 Describe the use of chiral auxiliaries to form the desired enatiomer
This is a chiral molecule which binds to the reactant, physically blocking on reaction site through steric hindrance, so ensuring that the next step in the reaction can only take place from one side. This effectively forces the reaction to proceed with a specified stereochemistry. Once the specific enatiomer of the new product has been set, the auxiliary can be taken off and recycled.
This is well researched blog! Greetings .Read more on - Medicinal Chemistry Services . Problem-solving Skills, Knowledge of the Latest Technology are a few important points that can help to get success in Medicinal Chemistry Research.
ReplyDelete