Methods In Drug Discovery Part 2

How are new compounds discovered - Isolate from natural sources - Modify compounds from natural sources - Observation of beneficial qualities (either expected or unexpected) during development - Rational design, based on knowledge of our target Define the term "drug" - A chemical substance that causes a change in an organism's physiology or psychology when consumed What may a medicine contain one or multiple of - APIs Define the term "herbal medicine" - Contains plants (or plant extracts) and may have a positive therapeutic effect; contains a mixture of many components Define the term "natural product" - A synthetically produced compound which is analytically identical to the naturally occuring compound - Contains plant or plant extract - May contain thousands or even millions of chemical compounds - Only some of these compounds have a positive therapeutic effect - Activity typically much lower than for pharmaceutical compounds; active ingredients "diluted" by other inactive comDescribe the differences between herbal ponents and pharmaceutical medicines - Contains purified compound(s) - May contain multiple compounds, usually not more than 2-3 in a single dosage form i.e. tablet - All active ingredients have an effect on the patient - Activity will be high and dependent on dosage 1/3 - Usually relies on methodical practical approaches; or observing unexplained beneficial effects - Clues can be taken from history (more shortly) What methods are used in drug discov- - Or screening can be used to identify the ery known to be expensive effect a compound (or extract) may have properties - Normally large compound libraries (100,000's) are tested against a target or a lead candidate is found using fragment-based screening - Extensive screening - Random screening - High-throughput screening - All of the above involve the testing State the number of ways of screening of of compounds against particular biologcompounds ical targets (e.g. whole animals, whole cells, isolated enzymes, isolated receptors) but differ in the philosophy of the testing - A process where a new chemical entity What is extensive screening in drug disis screened against a variety of biological covery targets - To ascertain if they have any interesting Why are many compounds subjected to medicinal properties, especially if they extensive screening are difficult to obtain - Central nervous system (CNS), cardioWhat types of pharmacological models vascular, pulmonary, digestive systems, are compounds screened against in exantiviral, antibacterial, and chemotheratensive screening peutic models What are phenothiazine derived amines - Chlorpromazine - Prochlorperazine - Trifluoperazine What did extensive screening detect in phenothiazine derived amines - Neuroleptic (anti-schizophrenic) properties were first detected by this approach 2/3 What did extensive screening detect in thiethylperazine - Was found to have antiemetic (anti-vomiting) properties What is random screening - Therapeutic objective is fixed with thousands of compounds tested against a small number of screens without regard to the structure of the compounds under test What significant antibiotics were discovered through soil sample examination in the 1940s/1950 - Streptomycin - Tetracycline What is taxol - Anti-cancer agent isolated the bark of Taxus brevifolia (a yew tree) in the 60s What screening method was used to - Random screening find compounds effective against cancer - Found to prevent microtubule synthesis: cells an essential process in mitosis - First clinical trials in 1989 required 27,000 kilograms of bark; since a typical 100 year old yew tree yields about 3 kiloWhat problem arose with sourcing taxol gram of bark, these trials required 9000 from the Pacific Yew tree trees - Collection of bark kills the tree, so use of taxol from its natural source would have threatened it with extinction What alternative source was found for taxol and what is its benefit - A precursor to taxol, 10-deacetylbaccatin III was found to grow in the needles of the European Yew - Taxus baccata in 0.1% yield - Does not require killing the tree State the use and benefit of semi-syn- - Uses protecting group chemistry thetic route synthesis of taxol - Reduces production costs significantly What is meant by a "semi-synthetic" route in chemical synthesis - Synthetically modifying a natural product to produce a final drug molecule 3/3