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Chapter 12 Target disease Priority for the Pharmaceutical Industry: Can the profits from marketing a new drug outweigh the cost of developing and testing that drug? Questions to be addressed: Is the disease widespread? (e.g. cardiovascular disease, ulcers, malaria) Does the disease affect the first world? (e.g. cardiovascular disease, ulcers) Are there drugs already on the market? If so, what are their advantages and disadvantages (e.g. side effects) Can one identify a market advantage for a new therapy? Drug targets A) Lipids Cell membrane lipids B) Proteins Receptors Enzymes Carrier proteins Structural proteins (tubulin) C) Nucleic acids DNA RNA D) Carbohydrates Cell surface carbohydrates Antigens and recognition molecules Between species: • Antibacterial, antifungal and antiviral agents • Identify targets which are unique to the invading pathogen • Identify targets which are shared but which are significantly different in structure Within the body: • Selectivity between different enzymes, receptors etc. • Selectivity between receptor types and subtypes • Selectivity between isozymes • Organ and tissue selectivity Bioassays (test systems) • Tests are required in order to find lead compounds and for drug optimisation • Need to be quick, easy and relevant • Tests can be in vivo or in vitro • A combination of tests is often used in research programs In vivo Tests • Carried out on live animals or humans • Measure an observed physiological effect • Measure a drug’s ability to interact with its target and its ability to reach that target • Can identify possible side effects • Rationalization may be difficult due to the number of factors involved • Transgenic animals - genetically modified animals • Drug potency - concentration of drug required to produce 50% of the maximum possible effect • Therapeutic ratio/index compares the dose level of a drug required to produce a desired effect in 50% of the test sample (ED50) versus the dose level that is lethal to 50% of the sample (LD50) In vitro tests • Tests not carried out on animals/humans Target molecules (e.g. isolated enzymes or receptors) Cells (e.g. cloned cells) Tissues (e.g. muscle tissue) Organs Micro-organisms (for antibacterial agents) • More suitable for routine testing • Measure the interaction of a drug with the target but not the ability of the drug to reach the target • Results are easier to rationalize - less factors involved • Does not demonstrate a physiological or clinical effect • Does not identify possible side effects • Does not identify effective prodrugs Testing drugs •High Throughput Screening •NMR •Enzyme Inhibition tests •Identify competitive or non competitive inhibition • Strength of inhibition measured as IC50 • IC50 = concentration of inhibitor required to reduce enzyme activity by 50% •Receptor tests •Not easy to isolate membrane bound receptors • Carried out on whole cells, tissue cultures, or isolated organs • Affinity - strength with which compounds bind to a receptor • Efficacy - measure of maximum biochemical effect resulting from binding of a compound to a receptor. • Potency - concentration of an agonist required to produce 50% of the maximum possible effect. The lead compound • A compound demonstrating a property likely to be therapeutically useful • The level of activity and target selectivity are not crucial • Used as the starting point for drug design and development • Found by design (molecular modelling or NMR) or by screening compounds (natural or synthetic) • Need to identify a suitable test in order to find a lead compound • Active principle - a compound that is isolated from a natural extract and which is principally responsible for the extract’s pharmacological activity. Often used as a lead compound. The lead compound A) The natural world B) The synthetic world C) The virtual world Plantlife (flowers, trees, bushes) Micro-organisms (bacteria, fungi) Animal life (frogs, snakes, scorpions) Biochemicals (Neurotransmitters, hormones) Marine chemistry (corals, bacteria, fish etc) Chemical synthesis (traditional) Combinatorial synthesis Computer aided drug design Identification of the lead compound A) Isolation and purification solvent-solvent extraction chromatography crystallization distillation B) Structure determination elemental analysis molecular weight mass spectrometry IR spectroscopy UV spectroscopy NMR (1H, 13C, 2D) spectroscopy X-ray crystallography Lead compounds from the natural world Plants Lead compounds from the natural world Morphine Poppy capsule Lead compounds from the natural world • OPIUM - Morphine • CINCHONA BARK - Quinine • YEW TREE - Taxol Lead compounds from the natural world Willow tree - salicylic acid O O OH OH OH Acetic anhydride O CH3 Aspirin O Coca bush - cocaine Me N CH3 CO2Me H N O CH3 C H O Procaine O C O NH2 Lead compounds from the natural world The beatons of pennycross THE BEATONS OF PENNYCROSS CURE for EPILEPSY Add a liberal sprinkling Flavour with essence Heat Simmer a cauldron for 20 of minutes water Produce one juicy spiders of dog turd until then warm enjoy to pedigree the touch dog Lead compounds from the natural world Herbal remedies of old Majority may have worked through a placebo effect Lead compounds from the natural world Rain forests Lead compounds from the natural world Coral and marine chemistry CH3 OMe S N CURACIN CH3 H H Lead compounds from the natural world Micro-organisms Lead compounds from the natural world Micro-organisms R OH O OH O OH H N O S O NH2 • • • • • H H OH Penicillin H Me ClHO NMe Cephalosporins Tetracyclines NH HN HN NH Streptomycin H N C NH H OH HO Chloramphenicol H N CH3 CH3 O CO2H 2 C H 2 HO H O2N CH2OH HN H 2 O C CHCl2 H H OH H O O CHO H Me OH H O O HO CH2OH H MeHN H H O H R C N H H S OAc N O CO2H H OH H Lead compounds from the natural world O Venoms and toxins C OH O C Teprotide O O H2N CH C N CH C H CH2 CH2 CH2 C O OH HN N O O C N CH C H CH2 CH2 N O O C N CH C H CH2 N O H N CH C N CH CH3 CH2 CH2 C O CH3 NH2 O CH2 C OH NH O C NH C NH2 HS N CH3 Captopril (anti-hypertensive) Lead compounds from the natural world Venoms and toxins Lead compounds from the natural world MeO Venoms and toxins N HO O H3 C H3 C H H O N OH OMe Tubocurarine (from curare) CH 3 CH 3 Lead compounds from the natural world MeO Venoms and toxins HO O H3 C H3 C H CH 3 N CH 3 H O N OH OMe Tubocurarine (from curare) MeO MeO N CH 3 O O C C O OMe OMe (CH 2)5 O OMe H N MeO OMe Atracurium (Neuromuscular blocker) OMe Lead compounds from the natural world Endogenous compounds Natural ligands for receptors OH HO OH H N Me HO H N Agonist HO HO ADRENALINE SALBUTAMOL NH2 HO NMe2 MeHN N H 5-HYDROXYTRYPTAMINE O Agonist S O N H SUMATRIPTAN Lead compounds from the natural world Endogenous compounds Natural ligands for receptors OH H N HO O OH Antagonist N H Me HO ADRENALINE PROPRANOLOL Me NH2 HN N HISTAMINE S HN N CIMETIDINE H N NHMe CN Antagonist Lead compounds from the natural world Endogenous compounds Natural substrates for enzymes Enkephalins Enkephalinase inhibitors Peptides Protease inhibitors H CO2H H2N O N H H N N H O L-Phe-L-Pro O O H N H H CONH2 SAQUINAVIR H N OH H N H H Lead compounds from the synthetic world SYNTHETIC COMPOUNDS Lead compounds from the synthetic world O H2N N N S O NH2 NH2 PRONTOSIL Lead compounds from the synthetic world O H2N S O SULFANILAMIDE NH2 Lead compounds from the synthetic world ONO2 ONO2 ONO2 Lead compounds from the synthetic world Rubber industry CH3 S H3C N C S S C S H3C Antabuse N CH3 4.4 Lead compounds from the synthetic world Organic synthesis 4.4 Lead compounds from the synthetic world Combinatorial synthesis Automated synthetic machines 4.4 Lead compounds from the synthetic world Combinatorial synthesis - peptide synthesis AMINO ACID RESIN BEAD AMINO ACIDS X PEPTIDE 4.4 Lead compounds from the synthetic world Combinatorial synthesis - heterocyclic synthesis RESIN BEAD N N Y O CHR1R2 4.4 Lead compounds from the synthetic world Combinatorial synthesis - heterocyclic synthesis N N RESIN BEAD R2 R3 O H 4.4 Lead compounds from the synthetic world Combinatorial synthesis - heterocyclic synthesis N N RESIN BEAD R2 R3 O R4 R5 EtO O 4.4 Lead compounds from the synthetic world Combinatorial synthesis - heterocyclic synthesis N N RESIN BEAD R2 R3 N R4 R5 HN O 4.4 Lead compounds from the synthetic world Combinatorial synthesis - heterocyclic synthesis N RESIN BEAD N Y R2 R3 N R4 R5 HN O 4.5 Lead compounds - impact of the human genome project The Past Lead Compound Targets The Present and Future Targets Lead compounds 4.5 Lead compounds - impact of the human genome project 4.5 Lead compounds - impact of the human genome project Lead compounds - impact of the human genome project 4.5 Lead compounds - impact of the human genome project 4.5 Lead compounds - impact of the human genome project 4.6 Lead compounds - de novo design 4.6 Lead compounds - de novo design X-RAY CRYSTALLOGRAPHY 4.6 Lead compounds - de novo design PROTEIN STRUCTURE 4.6 Lead compounds - de novo design Receptor CH3 IONIC BOND + H3N - Scaffold Scaffold Scaffold Scaffold Scaffold CO2 VDW BOND O HO H-BOND 4.6 Lead compounds - de novo design Thymidylate kinase inhibitors N H H N N N S O O O Optimisation O N N S N H2N O Anticancer agent O Lead compound 4.7 Design of lead compounds using NMR spectrosc NMR spectroscopy 4.7 Design of lead compounds using NMR spectrosc Binding Site Protein 4.7 Design of lead compounds using NMR spectrosc Protein No observable biological effect 4.7 Design of lead compounds using NMR spectrosc CH3 CH CH CH3 CH2 CH2 C 13C CH C NMR 4.7 Design of lead compounds using NMR spectrosc CH3 CH CH CH3 CH2 CH2 C 13C CH C NMR 4.7 Design of lead compounds using NMR spectrosc Protein Optimise epitope 4.7 Design of lead compounds using NMR spectrosc Protein Optimise epitope Optimise epitope 4.7 Design of lead compounds using NMR spectrosc Link Protein Optimise epitope Optimise epitope 4.7 Design of lead compounds using NMR spectrosc LEAD COMPOUND 4.7 Design of lead compounds using NMR spectrosc Design of a lead compound as an immunosuppressant OH O OMe N O O O MeO HO N H Epitope B OMe OMe Epitope A 4.7 Design of lead compounds using NMR spectrosc Design of a lead compound as an immunosuppressant OH O OMe N O O O MeO HO OMe OMe Lead compound N H