Drug+Design

Drug Design //presented by: Daniel Mulrow//

**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** **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.

-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.
 * Solid-Phase chemistry**: when a reaction occurs on an insoluble resin bead.
 * 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.
 * Solution-phase chemistry:** used to synthesize non-peptide drug molecules.

**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)** **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.

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)**
 * 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.

**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**
 * 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.



Pictures: Picture 1: [] 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 http://www.media.rice.edu/media/NewsBot.asp?MODE=VIEW&ID=9536 Pearson Baccalaureate Higher Level Chemistry IB Chemistry Study Guide by Geoffrey Neuss Chemistry, 3rd Edition by John Green and Sadru Damji
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