Serendipity And Drug Discovery Flashcards
What are the main examples of drug compounds discovered by serendipity ?
Penicillin
Cis-platin
Viagra
What is an example of an aspect of the drug discovery process which still relies in serendipity?
Screening compounds
How was cisplatin discovered?
An experiment was conducted using platinum electrodes to study the effects of electrical fields on the growth of E. coli. It was found that that this caused inhibition of cell growth.
Cisplatin is now used as an anticancer agent
How was Viagra discovered?
Originally developed as a treatment of angina and high blood pressure,
During clinical trials it was found that men did not return unused tablets,
Further investigation revealed a mechanism of action leading to Viagra being marketed as an anti impotence drug.
What is combinatorial chemistry?
A new methodology for synthesis which allows for the rapid synthesis of molecularly diverse compounds for biological testing.
This was developed as synthetic chemists could not supply enough compounds to keep the bioassays running efficiently (following the introduction of HTS which allowed bioassays to be performed on 10,000 compounds per month!)
What is iterative drug synthesis?
Individual drug synthesis.
This is very slow
What is the advantage of combinatorial chemistry?
We can take a shortcut in the biological testing process by combining pure compounds to give mixtures and simply testing the mixture, thus substantially saving time as it is much easier to perform a biological assay on 1 mixture of 1000 compounds than 1000 individual bioassays. This saves both time and money in the discovery of new drugs
What is combinatorial chemistry based on?
The notion that compounds should be synthesised and biologically evaluated as mixtures
What is the criterial of combinatorial chemistry?
Im just be reliable as we are trusting the making of chemical bonds
What is the process of combinatorial chemistry compared to iterative method in the making using 3 different amines and 3 different acid chlorides?
The iterative method would require preparation of the amides one at a time followed by purification and testing each one individually in the bioassay.
This may require 1 day to make each of the, totalling 9 days as there are 9 products. If you were mass producing 1 million analogues, this would take too long.
In the combinatorial method, we take a mixture of amides and react it with another mixture of acid chlorides to give a mixture of products (termed a library) this would produce a library of 9 amides which can be tested for biological activity. This means that instead of doing 9 separate syntheses we only have to do 1
What are some problems associated with the mixed reagent (combinatorial) method?
Dilution effects
Unreactive reagents
Synergism
What are dilution effects?
The activity of an active compound would be diluted by inactive components in the mixture therefore you would need to consider these effects.
With bigger matrices, the number of books in your library increases exponentially. Dilution effects would then become a major issue
Why is unreactive agents a problem with combinatorial chemistry?
Unreactive agents can lead to some books being missing.
There may be selective coupling of certain sets of ragents due to kinetics.
If all reagents do not to react then care must be taken to remove these chemicals otherwise you will be biologically testing reagents as well.
Thus, purification becomes difficult the larger the size of library we try to make
Why is synergism or inhibition a problem when it comes to combinatorial chemistry?
Some compounds may interact with each other in the bioassay so that the combination is active but individual compounds are not.
Similarly, one compound may oppose another compounds activity leading to a false negative
What is deconvolution?
The process of Identifying the active compound.
What is the main aim of deconvolution process?
To do as few reactions and tests as possible
How is the deconvolution process carried out using the library indexing method
Rather than making one big library containing all 9 compounds you prepare multiple sub libraries in which you hold one part of the molecule constant. (An indexed library)
E.g. A1 with B(1-3) Then A2 with B(1-3) Then A3 with B(1-3) Then start reacting B1 with A(1-3) Etc. this gives 6 sub libraries. We can then test each of these 6 sub libraries against our bioassay to determine the active component easily
Why is the library indexing method of deconvolution preferred?
We can test the sub libraries against our bioassay to determine the active component quite easily.
E.g. If two sub-libraries are found to be active, a table can be drawn and where the two sub libraries intersect will determine which compounds are active. This can be re tested by making more of the compounds,
What is the deletion strategy of sub library synthesis?
Involves removing one or more of starting materials from the mixture synthesis and test for biological activity.
Only the mixtures showing activity would be resynthesised leaving out one or more of the acid chlorides (one type of reagent)
This new mixture containing deletion a would then be tested for activity, if activity is observed it shows the acid chlorides were not essential for activity.
By process of elimination we can determine active molecule without synthesise and testing all individual compounds in the original library.
What is the main advantage of the deconvolution methods?
You do not need to synthesise all of the compounds of the target library to deduce which members of the library are active
What are the two main methods of deconvolution?
Library indexing method (to form sub libraries) Deletion strategy (process of elimination)
What is a major problem with deconvolution?
This arises when more than one active compound is detected.
The only way to solve this is to go back into the lab to find out if they are all active through re synthesis and re screening
What is one way of addressing some problems with making a mixture of compounds using conventional solution phase chemistry?
Move to solid phase chemistry
This is used for peptide/protein synthesis,
DNA and sugar chemistry
What are the disadvantages of solution phase synthesis?
Each individual compound is made step by step on the gram scale, each step requiring mg about a day with work up and purification steps, thus extremely inefficient at producing a wide range of diverse structures through HTS
