Drug design foundations Flashcards
What is the difference between a lead molecule and a candidate drug?
A lead molecule is the molecule that acts on a receptor. This receptor can be associated with a disease so this molecule is responsible for the activation of this receptor.
Identification of this lead molecule helps chemists then formulate a drug based on a lead molecule but adapting it to increase selectivity, solubility and reduce toxicity.
What is IC50?
It is how much drug is required to inhibit 50% of the specific enzymatic activity.
Why would you want the IC50 of a drug to be in the nano-molar range?
For a drug to be in the nano molar range when it is at a receptor, this means a suitable mass of the drug is consumed initially.
If the IC50 was above the nano molar range the initial mass consumed would be of too high a proportion e.g having bowls of cereal.
Outline the main approaches of drug discovery.
Natural products: molecules that are synthesized in plants and bacteria that would have an effect on humans.
Rational approach: modifying naturally existing agonists and antagonists to increase selectivity.
Evolution of existing drugs: Altering them to increase selectivity.
Library of existing drugs: continuation of drug testing of thousands of ‘useless’ drug molecules from university labs.
Serendipity: luck
What are some of the disadvantages using natural products to identify a lead compound and synthesize a drug molecule from?
In biological systems the lead compound acting on a receptor is highly complex and therefore has a highly complex synthetic route.
Low solubility
Highly degradable bonds- major problem as they candidate drug needs to be stable for shelf life and inside the body.
Explain the significance of Artemisnin.
Artemisnin is an anti malarial drug synthesized from Artemisia annua (a drug used as a traditional Chinese remedy for fever). It is a highly complex structure and very unstable so had to be modified.
Crucially due to high malaria cases being in third world countries it was only during times of war when Westernised countries financially invested into antimalarial.
Today the drug is grown on plantations in Africa so is only available for the native population as a treatment of Malaria- prevents Westernised companies ‘buying’ the drug.
Describe the significance of venom in the development of Captopril.
On attack pit viper’s venom kills by lowering the victim’s blood pressure too low. On realization scientists decided to modify the snake venom specifically the nonapeptide teprotide, reducing toxicity, to a drug that can be used to treat hypertension working on the same enzymes (angiotensin converting enzymes) and therefore become a ACE inhibitor.
What are sulfonamides and how do they work?
Sulfonamides are a group of antibiotics discovered in the 1930s. They work on the biochemical difference between bacteria and humans.
Humans naturally produce folic acid but bacteria synthesises it from p-aminobenzoic acid. During its replication sulfonamides compete for the reaction at the amine group. As a similar molecule it is recognised and incorporated into the molecule so that replication cannot occur at the carboxylic group preventing bacterial growth.
What are Me too drugs?
Essentially they are drugs made by competitive pharmaceutical companies to slightly modify a pre-existing drug for financial profit.
What is patent busting and give an example.
When a company designs a new drug they patent it which secures profit from the pharmaceutical revenue, the drug cannot be duplicated by a rival company or modified. Patent busting is other companies trying to bust the patent - finding ways to modify the drug in which other companies have not thought of.
An example of this is the development of Ranitidine from Cimetidine, both work as H2 antagonists but Ranitidine has minimal side effects in comparison (not a P450 inhibitor).
Compare structures of Salbutamol and Salmeterol.
Quite similar structures, major difference is the long aliphatic chain present in Salmeterol which enables it to bind to the receptor for longer. This therefore is used for patients who are more severely asthmatic and prevents them from having an asthmatic attack over night.
What is usually increased when medication is taken at a high dose?
The side effects
An example of this was on the brink of WW2 Sulfa-antibiotics were discovered and became crucial for treating minor infections on the frontline. However they were taken at a high dose that most of the patients experienced diuresis and low glucose levels.
Explain the process of exploiting the side effects of one drug in order to develop another.
The structure of one drug doesn’t just give one activity. Sulfonamides although used to treat bacterial infections gave side effects of diuresis and low glucose levels.
Diuresis is a method of reducing blood pressure. In glaucoma there is a build up of fluid behind the eye, increasing blood pressure. Diuretics work by increasing urine production, reducing fluids levels and therefore pressure. From sulfonamides diuretics such as Clorthizade were developed, still has the same sulfonamide groups.
The drug Tolbutamide was also developed from exploiting the side effects of high dosed Sulfonamides as an effective Diabetic drug to lower blood pressure.
What are pro drugs?
A pro drug is a drug that is not activated into a pharmaceutically active compound until it is metabolized in the human body.
Explain the concepts of in-vitro and in-vivo.
For a pharmaceutical drug if a compound is active in vitro it means the drug is active outside of the human body.
For a pharmaceutical drug if a compound is active in vivo it means the drug is active once metabolized by human body.
Is prontosil red active in-vitro?
In-vitro prontosil red is inactive. However when the drug is reduced by bacteria in the colon which excises the azo bond (-N=N-) it is metabolized and becomes active in-vivo.
What is an example of Serendipity?
Sildenafil under went clinical trials as it was in vitro able to treat angina and hypertension. However by listening to those who underwent the clinical trials, chemists realised that in-vivo the drug was metabolised and more effective for treating erectile dysfunction.
What is the pharmacophore?
Once the lead molecule has been identified, the pharmacophore needs to be identified. This is the part of the molecule that is absolutely essential for the activity of the drug.
Outline the process of identifying the pharmacophore?
Of the lead compound, multiple analoges are made. These are essentially slightly different versions of the lead compound (plus or minus a functional group).
Their structure activity relationship is then tested and by comparing them you can identify which parts of the lead compound is essential for activity and this is the pharmacophore.
What occurs after identifying the pharmacophore?
This is where there is a transition from chemists to pharmaceutics. The drug is then made into a better pharmaceutically active compound for example functional groups or carbon chains may be added in order to increase hydrophobicity, solubility and to ensure more selective binding.
What are the four guidelines of Lipinski’s rule of five?
Molecular weight equal to or <500
Log p equal to or <5
Number of hydrogen bond accepting groups equal to or <10
Number of hydrogen bond donating groups equal to or <5
What is the problem of only using one company for importing the drug?
The company will realise and put up the cost and make it very expensive to import. By using multiple companies they are forced to keep their prices down.
Why would some companies choose to make a new factory per new drug they discover?
If they know the profit from the drug in the market will outweigh the cost of building a new factory. An example of this was Taxol.
However most drugs this is not the case so it means that most companies will remain in the field of its expertise.
Outline the key differences between drugs binding to receptors and drugs binding to enzymes.
When drugs bind to receptors:
The ligand is structurally unchanged by the binding
The ligand can active or deactivate a mechanism
When drugs bind to enzymes:
Drug is usually chemically changed by binding
Drug normally inhibits the catalyzation of a reaction
How can drugs work chemically?
By neutralisation: antacids neutralise stomach acid, relieving symptoms for acid reflux and heart burn
By adsorption: morphine and caline solutions work in combination to treat diarrhea. Morphine bind to opoid receptors in the gut slowing down gut movements and then caline absorbs excess fluid.
Surfactants: used for premature babies whose lungs haven’t fully developed.
What did Crum, Brown and Fraser make the link between?
They realised that the chemical composition of a drug is responsible for its function.
Which theories were Ehrlich and Ing responsible for?
Paul Elrich- realised that some functional groups are directly related to the activity of a drug, they are crucial for their function. The role of a chemists is to modify these functional groups in order to make them potent, selective and safer for optimal pharmaceutical use.
Ing- realised that one functional group can have two opposite effects due to additional interactions. (Idea of agonists and antagonists).
