Sources of Active Compounds

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  • Created by: LBCW0502
  • Created on: 19-11-19 15:05
Outline the history of therapeutic medicine (1)
Therapeutic medicine was virtually non-existent until the end of the 19th century. People would take substances to relieve symptoms, no understanding of cells/diseases, biological molecules, no scientific understanding
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Outline the history of therapeutic medicine (2)
First edition of BP - 187 plant derived materials (mixtures), only 7 compounds purified (not a mixture), compounds only relieve symptoms (no pharmacological activity). Toxic compounds used to kill infection. Anaesthetics (diethyl ether, chloroform)
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Outline the history of therapeutic medicine (3)
Animal products also used e.g. lard, cantharidin (OTC wart treatment) and cochineal
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Outline the cell theory
Virchow. Thinking of living systems in terms of the function of their cells (understand how molecules affect them). Cells - tissues - organs - systems, functions and physiological state (people thought infections spontaneously happened)
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Outline the germ theory
Particular microbes are pathogenic to humans, accounted for many forms of disease e.g. anthrax, cholera, rabies. (Concept of pharmacology - start to target specific cells, not just relieve symptoms, molecular biology not known yet)
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Outline developments in chemistry
Theory of bond-bond formation and valency (how many bonds an atom could form) - understand chemical structures (in order to develop compounds). First therapeutic drug from synthetic chemistry (amyl nitrate - vasodilator)
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What does the term 'magic bullet' mean?
Link between cells and chemicals. Able to make a chemical to alleviate symptoms/disease. Molecule with specificity against disease/against cell e.g. Ehrlich's compound to treat syphilis (screen compounds to find activity)
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Describe features of the sulphonamide story (1)
Specific chemical structure, specific treatment for certain disease (antibacterial). Principle of target specific drug activity (target bacterial cells not human cells)
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Describe features of the sulphonamide story (2)
Prontosil administered in patients with infection, patients getting better. Looked at prontosil after administration (metabolism/excretion)
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Describe features of the sulphonamide story (3)
Compound broken down into sulphonamide (PABA competitively inhibits dihydrofolate reductase. Basis of drug toxicity, enzyme in bacteria has different amino acid sequence to enzyme in human
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Describe features of the sulphonamide story (4)
Sulphonamides excreted in kidneys (discover compounds used in kidney disorders e.g. furosemide). Range of compounds discovered from range of therapeutic targets
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Give examples of lead molecules discovered through metabolism studies (1)
Diazepam (BDZ) metabolised by CYP450 to nordazepam and oxazepam (used as individual compounds in their own right depending on properties). Temazepam (more polar than diazepam, used for depression due to the way compounds are metabolised)
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Give examples of lead molecules discovered through metabolism studies (2)
Temazepam, faster onset of action, shorter duration of action. Used in insomnia (diazepam used as anxiolytic agent). Patients feel sleeping after taking temazepam (but no hangover next morning as most of the drug is excreted by this time)
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Describe features of other target directed approaches to drug design using sulphonamides (1)
Hitchings-Elion – consider analogues of sulphonamide, effects on different pathways which dihydrofolate reductase is involved in. Consider DNA synthesis (nucleotide bases). Apply principle from antibacterial therapy to anticancer therapy
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Describe features of other target directed approaches to drug design using sulphonamides (2)
(Antivirals e.g. acyclovir, AZT come form marine natural sources)
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Describe features of other target directed approaches to drug design
Development of competitive antagonists e.g. propranolol (beta blocker)
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Describe features of rational drug design - molecular pruning
Try to obtain a new lead molecule of change the activity profile of an existing one (complex natural product) by chopping away portions of a biologically active molecule to try to evaluate the pharmacophore
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Describe features of rational drug design - conformationally restricted analogs (1)
In some cases an increase in structural complexity/rigidity can lead to increased potency (and a new drug product). Increased rigidity of the molecule decreases degrees of freedom for rotation, enhancing interaction with receptors
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Describe features of rational drug design - conformationally restricted analogs (2)
E.g. Subutex - for opiate management
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Describe features of rational drug design - functional group manipulation (1)
Substitution of atoms and ring systems with different ones of similar shape, volume and electron distribution/charge. Can change inhibitor to agonist and vice versa. Can change ADME or ADMET characteristics significantly
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Describe features of rational drug design - functional group manipulation (2)
Used to create Me-Too and Follow-On products.
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Describe features of rational drug design - conjugates
Joining two entities together to obtain a synergistic therapeutic effect, a formulation/delivery benefit or for targeting purposes
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Describe features of rational drug design - structural biology/molecular modelling/virtual screening (1)
One of the best ways to discover a new lead molecules. Knowledge about the pathophysiology of a disease used to discover new target e.g. transmitter, enzyme, receptor, signalling pathways relevant to disease. Computational methods
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Describe features of rational drug design - structural biology/molecular modelling/virtual screening (2)
Structure of protein/enzyme/receptor linked with signalling pathway (use X-ray, NMR). Physical assay established (HTS). Agonists/antagonists identified by screening/hit-to-lead. In silico screening to produce further hits. E.g. Gleevec (anticancer)
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Describe features of rational drug design - structural biology/molecular modelling/virtual screening (3)
Work out structure of target (e.g. protein receptor on surface of membrane), consider 3D structure of receptor, find out which molecules will interact in the chemical space, compound libraries screened during computer aided drug design
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Give an example of a lead molecule discovered through serendipity
Sildenafil originally developed as an anti-hypertensive agent, but S/E led to present indication of male erectile dysfunction. Tadalafil for pulmonary HTN and BPH - e.g. of drug respositioning
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What is a natural product? (1)
Anything that is produced by life, includes biotic materials (wood, silk), bio-based materials (bioplastics, cornstarch), bodily fluids (milk, plant exudates) and natural materials once found in living organisms (soil, coal)
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What is a natural product? (2)
Any organic compound that is synthesised by a living organism
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What is synthetic organic chemistry and semi-synthetic chemistry?
Synthetic organic chemistry - science of organic chemistry, origins in study of natural products, create organic molecules in the laboratory. Semi-synthetic organic chemistry - scientists modify existing natural products to improve/alter activities
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Describe features of natural products (1)
High structural diversity, unique pharmacological/biological activities due to natural selection/evolution. Structural diversity exceeds capabilities of synthetic organic chemists. Natural products used as starting points for drug discovery
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Describe features of natural products (2)
Followed by synthetic modifications to help reduce S/E and increase F. Natural products/derivatives used in food additives/spices/herbs/antibacterial agents/antioxidants to preserve food. Natural products used in clothes, plastics, rubber products
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Describe features of natural products (3)
Natural products used in health and beauty products, energy used to power automobiles Limited computational resources to identify new receptors. Human genome (not successful strategy)
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What is bioprospecting?
The process of searching for and finding new natural products throughout the world
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What is pharmacognosy?
The discipline that elucidates the structure of natural products and studies their biological activity
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What are the three main sources of natural products?
Plants and trees, bacteria/fungi and marine organisms
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What is the original source of statins?
Cholesterol lowering agents from fungal sources, unsure about significance of the use in fungi. Targets HMG-CoA reductase
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Describe features of plants and trees (1)
Organic chemists. Produce large numbers of organic molecules (complex, rich in stereochemical centres). Reasons for production often unknown (could be attack/defence weapons). Isolation of active ingredient can be challenging
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Describe features of plants and trees (2)
Clinical activity can be a mixture of compounds. Can be cultivated so can be used for commercial production of drugs. Madagascar periwinkle (Vinca rosea), Vinca alkaloids (anticancer treatment, doesn't follow LRO5, not all drugs apply)
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Describe features of plants and trees (3)
Pacific Yew tree (Taxus brevifolia). Paclitaxel (Taxol) - microbial symbiosis (fungi in roots produce drug)
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Describe features of plants and trees (4)
Taxol – stabilizes microtubules, daughter cells can't separate/complete cell division (cancer – cells replicate rapidly, selective drug toxicity, inhibit cell division in rapidly dividing cells compared to normal cells)
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Describe features of bacteria and fungi (1)
Prolific, sources of successful drugs in their own right, modern drug discovery. Golden age in antibiotic drug discovery. Most antibiotics developed in 50s/60s e.g. streptomycin for TB. Fleming (penicillin). Some compounds not antimicrobial
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Describe features of bacteria and fungi (2)
Teicoplanin – prevents rejection of organs in transplantation. Avermectin – anti-parasitic, used in cattle. No new sources - market saturation, compounds to complicated (no economical benefit, cannot supply demand)
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Describe features of bacteria and fungi (3)
Recollection (compounds not always found in nature, depends on physiology of organism)
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What are the most common diseases of the Western World?
Disease of lifestyle e.g. heart disease, cancer. Shift in pharmaceutical business – want to invest in treatments for long term illnesses (metabolic illnesses) e.g. statin to lower cholesterol levels, to make money
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Describe features of marine animals and symbionts (1)
Limited knowledge about organisms in the ocean. Development of scuba equipment – breath at depth, go deeper into the ocean, discover life in the ocean
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Describe features of marine animals and symbionts (2)
Understand how organisms interact with themselves/environment, produce compounds to live in ecological niche and to prey on another animals/deter predation. Invertebrate sources used
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Describe features of marine animals and symbionts (3)
Trabectidin (Yondelis) - DNA binding agent, alkylates N2 of guanine in minor groove to form bulky adduct which blocks DNA processing, has in vitro activity against melanoma/breast/ovarian/colon/non-small cell lung/prostate carcinoma cell lines
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Describe features of marine animals and symbionts (4)
Also used against soft tissue sarcomas. Issues - supply (not able to meet demand, conservation/extinction
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How are the issues with sources of natural products overcome? (1)
Invertebrates are associated with micro-organisms during their lifetime. Microbial compounds, not animal compounds (not invertebrate). Able to culture microbes (but few can be cultured on synthetic media)
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How are the issues with sources of natural products overcome? (2)
Use cloning/biosynthetic pathway, recombinant genes to overcome supply issue
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Card 2

Front

Outline the history of therapeutic medicine (2)

Back

First edition of BP - 187 plant derived materials (mixtures), only 7 compounds purified (not a mixture), compounds only relieve symptoms (no pharmacological activity). Toxic compounds used to kill infection. Anaesthetics (diethyl ether, chloroform)

Card 3

Front

Outline the history of therapeutic medicine (3)

Back

Preview of the front of card 3

Card 4

Front

Outline the cell theory

Back

Preview of the front of card 4

Card 5

Front

Outline the germ theory

Back

Preview of the front of card 5
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