Drug Discovery 1 Flashcards
What is a lead compound?
The improved molecule via physicochemical, pharmacologic, toxicologic, and pharmacokinetic modifications of a “hit”
What might biologists discover?
A novel biological target
- an enzyme
- a receptor
What is a drug?
A molecule that can be designed and synthesised
What are the two classes of drugs?
Chemical drugs
Biological drugs
Describe chemical drugs.
Chemical Drugs
Range from simple inorganic salts to complex organic molecules.
Organic drug molecules often referred to as small molecules these are ‘drug-like’ organic compounds with a molecular weight approximately < 500.
When discovered, referred to as a ‘New Chemical Entity’ (NCE).
Describe biological drugs.
Biological Drugs (“Biologics”).
Also known as large molecule drugs. Usually proteins such as peptides or antibodies (but could be a nucleic acid, e.g. gene therapy).
When discovered, referred to as a ‘New Biological Entity’ (NBE).
What is a small organic drug referred to once discovered?
A New Chemical Entity (NCE)
What is a large molecule drug referred to once discovered
A New Biological Entity (NBE)
What are New Chemical Entities and New Biological Entities known as when considered together ?
New Molecular Entities (NMEs)
Where do novel Small Molecules come from?
Natural sources or derived from nature Derived from endogenous compounds - biochemical Synthetic drugs - derived from screening or rational medicinal chemistry Serendipity 'Me too' In silico drug design - molecular modelling
Why are small lead compounds often not suitable drug molecules?
Do not have suitable properties to use clinically
- poor aqueous solubility
- low activity
Usually require optimisation
Historically, what was the only source of medicines?
Nature
- herbal medicine
- Chinese medicine
- minerals
- mercury
- arsenic
What is a Natural Product?
A discrete compound produced by a living organism
- very valuable to medicine
Give examples of medicinal natural products that have been derived from plants
Paclitaxel- breast and ovarian cancer.
Isolated from bark of the yew tree.
Quinine- malaria.
Isolated from bark of cinchona tree
Digoxin - Digoxin, heart failure, arrhythmias.
Leaves of the Foxglove.
Morphine- analgesic.
Contained within resin from poppy seeds.
Give an example of a drug that is derived from a natural product
Aspirin
- willow bark used from 400BC to relieve fever
How is salicin converted into aspirin?
Hydrolysis removes sugar group
Oxidation -> salicylic acid
Acetylation -> aspirin
How is morphine converted to diamorphine?
Acetylation
Why might biochemicals or natural ligands within the body not make good lead compounds prior to analogue synthesis?
Natural ligand may
- have undesirable duration of action
- be excreted or metabolised too quickly
- be chemically unstable
Why are small lead compounds often not suitable drug molecules?
Do not have suitable properties to use clinically
- poor aqueous solubility
- low activity
Usually require optimisation
Why might biochemicals or natural ligands within the body make good lead compounds after analogue synthesis?
Natural ligand beforehand may
- have undesirable duration of action
- be excreted or metabolised too quickly
- be chemically unstable
What does changing the structure of an endogenous lead compound allow?
Determination of structure activity relationships (SAR)
Why must analogues of natural ligands retain their core structures?
Allow binding to the biological target
What is methotrexate?
Anti-proliferative drug
- blocks the effect of folic acid
- essential for cell growth
Discovered from a collection of compounds all with structural similarities to folic acid
Which synthetic derived drugs were noted for their anti-bacterial properties in the early 1900s?
azo dyes
What was added to azo dye to increase the binding of the dye to the wool?
Sulphonamide group
- SO2NH2
What did the sulphonamide azo dye compound decompose into?
Sulfanilamide
- an excellent antibiotic
Why are sulphonamides now largely discontinued as antibiotics?
Resistance
Side effects
More effective agents available
What is sulfadiazine still used for?
Rheumatic fever
a disease that can affect the heart, joints, brain, and skin. Rheumatic fever can develop if strep throat and scarlet fever infections are not treated properly.
What is co-trimoxazole (Sulfamethoxazole and Trimethoprim) currently used for?
Pneumonia and Toxoplasmosis
Pneumonia is an infection that inflames the air sacs in one or both lungs
Toxoplasmosis is a common infection that you can catch from the poo of infected cats, or infected meat
flu like symptoms
How many molecules were screened whilst trying to find a better inflammatory alternative to aspirin or corticosteroids in the 1950s?
Ibuprofen, marketed in 1969 was non-toxic (no liver accumulation) and safe (non-prescription in 1983). Approximately 20 years to develop, from the synthesis and screening of 650 synthetic analogues.
Give an example of a drug discovered using computer aided (in silico) drug design
Tamiflu
What was the lead compound in developing Tamiflu?
Sialic acid
- a computer model showed it interacted with neuraminidase by bonding to three arginine residues via a carboxylic acid group
- the target viral enzyme
What is Tamiflu?
An ethyl ester prodrug allowing oral formulation
- ester is cleaved by plasma esterase enzymes to unmask the important carboxylic acid
What are the advantages to ‘me too’ drug design?
An easy way to design a drug cheaply is to copy another product
What is a ‘me too’ drug?
One with a similar structure to an existing drug, modified enough to make the compound novel but not so much that the activity is affected
what does serendipity mean ?
Serendipity “the occurrence and development of events by chance in a happy or beneficial way”
Give an example of a Serendipitous drug design?
Penicillin
- 1928 Alexander Fleming goes on holiday
- spores from Penicillium mould contaminate a culture plate containing Staphylococci bacteria
- the penicillium mould kills the bacteria on contact
- a chemical in the mould is killing the bacteria
1939 - active substance finally isolated
1944 - used in the clinic
Give an example of a drug discovered by utilising side effects
Sulfanilamide caused hypoglycaemia
- low blood sugar
It was also a mild diuretic
Led to development of tolbutamide (diabetes) and chlorothiazide (diuretic)
What is a pharmacophore?
Portion of a drug required for activity
If the pharmacophore is altered or absent the molecule will lose the associated properties.
How did sildenafil become the drug commonly known as “viagra” through the use of its side effects?
Sildenafil was designed as a vasodilator to treat angina and hypertension
1992 - performed very poor in clinical trial to treat coronary heart disease
30 men refused to return unused medicine
- beneficial and unknown side effect
- 1998 - drug launched as a treatment for erectile dysfunction
