Drug Designpresented by: Daniel Mulrow

A chart summarizing the steps to make a drug.
A chart summarizing the steps to make a drug.

Modern Drug Design
-knowledge of how drugs work has improved drug design
-Rational Drug Design:research is focused on identifying target molecules in the body and creating drugs to interact with them.
-Old Drug Design was trial and error based

Lead Compounds  (Not the element Lead)
-A lead compound is one that gives the best pharmaceutical results.
-This compound is used as a start for the development process and drug design.
-Compound Libraries: details on the different combination of the lead compound with various candidate molecules stored for future reference.

Different Types of Drug Design and Drug Testing
Combinatorial Synthesis
Example of how Combinatorial Synthesis
Example of how Combinatorial Synthesis

What? A method for synthesizing large libraries of compounds simultaneously (Library size range 10,000-500,000). This method allows scientists to create thousands of complex materials in the same amount of time it used to take a scientist to create one.
How? Synthesis occurs on a small scale with the help of specially designed machines that generate a pool of chemically similar compounds. All reaction
s take place in separate vessels with a defined reaction route for each. It mimics random mutation because the strongest or best compounds are chosen by the scientists.

Solid-Phase chemistry: when a reaction occurs on an insoluble resin bead.
Mix and Split Method
Mix and Split Method

Mix and Split: Three components are first linked to a resin bead. The resin bead is then mixed into another pool of components which then attach to the resin bead. This can be done to incorporate numerous components together yielding many different combinations.
-This Technique is best used to link together amino acids to create peptide libraries. Because peptides are not always desired as drugs (due to the fact that they can't be taken orally) other techniques can be used to make drugs as well.
Solution-phase chemistry: used to synthesize non-peptide drug molecules.

Parallel Synthesis
Example of Parallel Synthesis
Example of Parallel Synthesis

What? A method for synthesizing focused libraries of compounds. (Library size is much smaller than Combinatorial and there is a single product in each reaction flask compared to multiple). It is used to research drug structure for optimization. It is becoming a much more popular form of synthesis than combinaotrial.

How? Each flask starts out with one compound and each subsequent step adds the same compound to each
flask, this creates similarly chained compounds with one varying element.

Teabag procedure: porous bags of reins are suspended in reagents.

 High-throughput screening (HTS)

A HTS lab
A HTS lab
What? The use of robotics and micro-scale chemistry to boost efficiency of testing these compounds. This process can test as many as 100,000 compounds in a day.
How? Each test has an easy way to measure the reaction such as watching the color change or displacement of a labeled ligand.

The structure of Gleevec
The structure of Gleevec
Example from text:The inhibitor for the Tyrosine Kinase enzyme, a key component of leukemia, was found and through the use of HTS 2-phenylaminopyrimidine was identified as a lead compound. The drug Gleevec® was created with modifications to this inhibitor and it is one of the first anticancer drugs to ever be designed (that works).

Computer-Aided design (CAD)
Use of CAD to create a model of the CYP11B2 binding site with bound inhibitor.
Use of CAD to create a model of the CYP11B2 binding site with bound inhibitor.

What? The use of molecular-modeling software to analyze the interactions between drugs and their receptor sites. The use of X-rays and Nuclear magnetic resonance have become very popular in CAD.

Pharmacophore: the part of the drug responsible for specific binding and activity of the drug.

3-D pharmacophore: a model acquired from pharmacophore mapping; a process used when the receptor site is not known. This is done by using software to predict the most likely 3-D structure based on similar molecules. This structure shows the arrangement of functional groups required in the drug. These structures are then stored in a database that can be used to help identify new structures in the future.

Example from the text: CAD has been used to help treat the HIV/AIDS virus. Through CAD and 3-D pharmacophores a drug was designed and tested using X-rays that confirmed the drugs abilities to bind to the target in the virus.

Goal:  To reduce the total number of synthesized molecules. To begin using virtual drug trials.

Graph demonstrating Bioavailability of Paracetamol in an adult
Graph demonstrating Bioavailability of Paracetamol in an adult

Different Drug structures used to maximize absorption and distribution
Bioavailability: the amount of a drug (in a percentage) that is in the bloodstream. It generally ranges from 20%-40% because of misdirection or absorption within the body. While in the blood, drugs are transported in the plasma. Drugs that are more polar or have ionic groups are more soluble in the blood's aqueous solution therefore allowing them to be administered to their target cell more efficiently. Drugs can be modified to increase their bioavailability. Molecules containing an acid or base group can be easily modified to allow for easier absorption.

 Reaction of Carboxylic Acid to form ionic salt

When aspirin reacts with a strong alkali it will form a salt. The carboxylic acid group attached to the aspirin will be converted to its conjugate base increasing aspirin's solubility in an aqueous solution (known as Soluble Aspirin).

Reaction of Amine to form ionic salt

When a drug with an amine group reacts with a strong acid (normally HCl), it can be converted into its chloride salt making it more soluble in an aqueous solution. An example of this is Prozac® which is the chloride salt of fluoxetine.

Asymmetric Synthesis - Single Enantiomer
Taxol structure
Taxol structure

Asymmetric synthesis (AKA Enantioselective synthesis): A way to directly synthesize a single enantiomer. This becomes useful when the specific enantiomer desired can be created without creating other (waste) enantiomers. In order to do this type of synthesis chiral auxiliaries are used.

Chiral Auxiliary: A chiral molecule that binds to a reactant and blocks one reaction site through steric hindrance, ensuring that the next step of the reaction can only occur at one side. This can ensure that a specified product will be created. These can be recycled once the reaction is complete.

Real world application: The anticancer drug Taxol® has 11 chiral carbon centers and requires a very specific synthesis route in order to be created. Titanium and rhodium are used as chiral auxiliary to produce a good yield of the single enantiomer required to make Taxol.

Another chart summarizing the joys of drug design
Another chart summarizing the joys of drug design

Picture 1: http://www.biosolveit.de/science/
Picture 2: http://www.answers.com/topic/combinatorial-synthesis
Picture 3: http://journals.prous.com/journals/servlet/xmlxsl/pk_journals.xml_summary_pr?p_JournalId=2&p_RefId=857183&p_IsPs=N
Picture 4: http://pubs.acs.org/subscribe/archive/ci/31/i11/html/delue_fig2.ci.html
Picture 5: http://www.uniconnect.com/home/applications/hts/
Picture 6: http://www.media.rice.edu/media/NewsBot.asp?MODE=VIEW&ID=9536
Picture 7: http://www.mpi-inf.mpg.de/departments/d3/areas/docking.html
Picture 8: http://www.eurosiva.org/Archive/Lisbon/SpeakerAbstracts/Intravenous%20pro.htm
Picture 9: http://nl.wikipedia.org/wiki/Bestand:Aspirin.png
Picture 10: http://www.pharmacy-and-drugs.com/reviews/Fluoxetine.html
Picture 11: http://pubs.acs.org/subscribe/archive/mdd/v04/i09/html/09willis_fig1.html
Pearson Baccalaureate Higher Level Chemistry
IB Chemistry Study Guide by Geoffrey Neuss
Chemistry, 3rd Edition by John Green and Sadru Damji