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Chemistry- Drug Design
Transcript of Chemistry- Drug Design
D.9.2 Explain the use of combinatorial and parallel chemistry to synthesize new drugs
D.9.3 Describe how computers are used in drug design
D.9.4 Describe the use of chiral auxiliaries to form the desired enantiomer HIGHER LEVEL Erik Hunder 3rd Hour Modern Drug Design - Drugs work by attaching to a biological molecule in the body (enzymes, DNA, receptor, etc.) to prevent the development of a disease - Drugs used to be designed on mostly a trial-and-error basis, but now, pharmaceutical companies use rational drug design - Drug design is a complex field that is constantly advancing Lead Compounds -Desired compounds are found using compound libraries (set of compounds stored along with details of the molecules' activities) -Methods for finding compounds: Combinatorial Synthesis
High-Throughput Screening -Lead Compound- Compound that shows desired pharmeceutical activity needed for a drug Combinatorial Synthesis -Used to make large groups of compounds (combinatorial libraries) rather than making compounds one by one -Specially designed machines are used to make a large amount of compounds in a short period of time -Reactions occur on a very small scale, in separate vessels, using a variety of starting materials, and reagents. -Products are screened for the desired activity to hopefully find a lead compound to be used for a drug -Reactions usually occur via solid-phase chemistry - Reactions occur on a resin bead, and once complete, the product is cleaved from the bead + + + + Cleave Product -Mix and split method used to create a variety of products - Linking together amino acids creates a large variety of peptides - Peptides usually aren't desired for drugs taken orally because they are broken down before they reach the blood stream - However, solution-phase combinatorial chemistry can be used to synthesize smaller, non-peptide drug candidate molecules Parallel Synthesis -While combinatorial synthesis produces a mixture of products in each flask, parallel synthesis produces a single product in each flask - Produces a more focused and less diverse library - Usually involves a series of simple steps to produce a highly reactive intermediate. This is then reacted with a number of different reagents. -Teabag procedure- porous bag of resins are suspended in reagents - Parallel synthesis is used when separate testing of each compound is necessary - Parallel synthesis is becoming increasingly popular in the pharmaceutical industry while combinatorial synthesis is seeing a decline High-Throughput Screening - Compounds can be tested efficiently through the use of robotics and micro-scale chemistry - Compounds are tested against of large number of different targets and large amounts of data are produced -Tests are designed to give a measurable effect (color change, displacement of a ligand) Computer-Aided Design (CAD) -Molecular-modelling software analyzes the interaction between the drug and the receptor site to help get the optimal fit - Pharmacophore- part of the drug molecule responsible for specific bonding and activity - 3-D Pharmacophore model can be done by analyzing molecules that bind to the desired receptor, searching for common features, and using software to predict the most likely structure - 3-D model shows arrangement of functional groups required for the drug - Molecules with similiar structures can be found using a searchable database - Major goal of CAD is to reduce the amount of molecules that have to be synthesized and tested - Virtual trials are beginning to replace lab trials in the development of drugs Modification of Drug Structure - Bioavailability- percentage of drug that actually reaches the bloodstream -This is typically pretty low (20-40%) as drugs may be misdirected or broken down before absorption - Drugs that are more polar or have more ionic groups can dissolve easier into the bloodstream and be distributed to target cells more effciently - Some drugs can be modified by incorporating an ionic group into their structure to make them more soluable Reaction of a -COOH acid group - Strong alkali reacts with the carboxylic acid group to form its conjugate base - Increases aqueous solubility of compound - Example: Aspirin + Na OH ---> + H2O Sodium salt of aspirin is more soluable Reaction of a -NH2 basic group - Strong acid (usually HCl) reacts with the amine group to form its conjugate acid - Increases aqueous solubility of compound - Example: Prozac (fluoxetine hydrochloride) Fluoxetine hydrochloride (Prozac) is more soluable + HCl ---> NH2+Cl- Asymmetric synthesis - Synthesis forms a racemic mixture of a chiral compound, but often only one enantiomer is wanted - Instead of trying to separate this mixture and waste product, asymmetric synthesis (or enantioselective synthesis) is used -This can be done using chiral auxiliary:
-a chiral molecule is bound to the reactant, blocking one reaction site and ensuring the reaction can only take place on one side.
-This forces the desired steriochemistry to be produced.
-Afterward, the chiral auxiliary is removed and recycled. Testing Drugs -First, in-vitro testing (in glass) is done, then in-vivo testing (in living) is done -Tested in animals before humans - 3 Phases of Clinical Trials Phase 1- 10-100 healthy volunteers tested for side-effects Phase 2- 50-500 patients with the disease are tested Phase 3- Several hundred-Several thousand patients tested exactly the way the drug is to be administered on the market FDA Approval - Drug must be proven safe and effective by the FDA - Even after approval, drug is carefully monitored by FDA -Once approved, the drug has a 17-year patent - Next steps are marketing, manufacturing, possible withdrawals and recalls Sources Brown, Catrin and Ford, Mike , IB HL Chemistry, Pearson Education Limited 2009 Pearson, Drug Design Testing Manufacturing and Marketing, <http://wps.pearsoncustom.com/wps/media/objects/10490/10742713/HC115_Ch02.pdf> Chang, Young-Tae, Chemical Library <http://ytchang.science.nus.edu.sg/book/html/e007.html Jefferson, Norvell, From Molecule to Medicine <https:/www.youtube.com/watch?v=d9ouk_46xA8> PhRMAPress, The Drug Discovery Process, <https:/www.youtube.com/watch?v=d9ouk_46xA8> Drug Design and Development <http://www.merckmanuals.com/home/drugs/overview_of_drugs/drug_design_and_development.html>