Where do drugs come from?

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Presentation given by David Livingstone to the Isle of Wight Cafe Scientifique about the origins of drugs.

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Where do drugs come from?

  1. 1. Where do Drugs Come From? David Livingstone ChemQuest, Sandown, UK & Centre for Molecular Design, University of Portsmouth, UK ChemQuest
  2. 2. DL BackgroundFirst degree in chemistry and then a Ph.D.funded by the Wellcome foundation Ltd.Went to Wellcome and worked onhaemoglobin and drug designJoined SmithKline Beecham to run a drugdesign groupSet up a consultancy in 1995Www.chemquestuk.com,davel@chemquestuk.com ChemQuest
  3. 3. What do we mean by “drug”Broadly speaking, any substance which whentaken into a living organism alters ordinarybodily function.An exogenous compound (synthetic, semi-synthetic or natural) used to treat, cure,prevent or diagnose disease or to otherwiseenhance physical or mental well-being ChemQuest
  4. 4. Natural SourcesPlants – bark, leaves, seeds, fruits......Insects – parts, dried, ground, boiled...........Animals – parts, blood, faeces, cooked.......Microorganisms such as fungi, yeasts andbacteriaSea creatures – more unusually ChemQuest
  5. 5. Drugs from Natural ProductsMany naturally derived drugs have been in usefor thousands of yearsWell known examples are: Morphine (~4000 B.C.) Reserpine (<1000 B.C.) Aspirin (~400 B.C.) Hippocrates – willow tree bark & leaves Ephedrine (<1 A.D.) Quinine (<1650) Digitalis (1775) ChemQuest
  6. 6. More Recent Drugs from Natural ProductsCyclosporinMevinolin (HMG CoA Reductase)Captopril, Enalapril (snake venom)Taxol (winner R&D 100 award 1995)Integrilin (anticoagulation - approved 1998) ChemQuest
  7. 7. Industrialisation of Drug DiscoveryThe development of organic chemistry allowed us to find out the molecular structure of theactive ingredients of “cures” after a bit ofdetective workThe first drug companies developed fromindividual pharmacists making new moleculesthat “looked like” the natural onesTesting process took a little bit longer tochange – Bayer antimalarial programme! ChemQuest
  8. 8. Origins of the companiesFirst known drugstore opened in Baghdad in754.Merck started as a pharmacy founded inDarmstadt in 1668GlaxoSmithKlines origins go back to 1715Beecham started industrial production in 1842Pfizer – 1849, Colonel Eli Lilly served in theunion army in the civil war ….................. ChemQuest
  9. 9. Drug DiscoveryDrug research in the companies was mainlystructural analogues of natural products orother companies drugs until the late 1970sLimited exploration of natural products – e.g.seaweedsChemists knew about some important physico-chemical properties such as solubility,molecular weight and a tendency to dissolve inolive oil!! ChemQuest
  10. 10. Drug TargetsApart from enzymes, the place where drugs“worked” in the body was often called areceptorWe had no idea about the structure ofreceptors – they were just labelled accordingto their effects e.g. the β-adrenergic receptorThe oxygen transport protein haemoglobin wasa notable exception to this. ChemQuest
  11. 11. Molecular ModelsInformation about the size of atoms, length ofbonds and “shape” of molecules from X-raycrystallographyThis allowed the production of various kinds ofphysical models of molecules ChemQuest
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  14. 14. How do Drugs Work ?They interfere with some process in the bodyThis is achieved by Interaction - withhormones, proteins, enzymes and so onWhat controls this interaction ?Size, shape and other properties of themolecules ChemQuest
  15. 15. Narcosis of Tadpoles -1899 ChemQuest
  16. 16. Design Without Knowledge of TargetProperties of the drugs will control interactionat the target and hence efficacyImportant properties are: Lipophilicity Steric (size & shape) ElectronicForms the basis of a mathematical approach ChemQuest
  17. 17. What is QSAR ? R π log 1/C H 0.0 0.5 Me 0.56 1.1 R Cl 0.71 1.8 OH -0.67 0.1 C6H5 1.96 2.4 ChemQuest
  18. 18. Drug design - QSAREarly approaches were restricted tocongeneric series using (limited) tabulateddescriptors, e.g. : 1 log =a . p+b . s +c . MR+d C ChemQuest
  19. 19. Drug Design - 1980sThere were 2 approaches: Molecular models based on targets QSAR based on drugsAs computers became more powerful softwarereplaced the physical modelsIt gradually dawned on people that the 2methods should be combined ChemQuest
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  21. 21. Computer ModelsTreats molecules as balls (atoms) joined bysprings (bonds)The energy of the system is computed by a “forcefield”: N E=∑ f (r 0−r i , j )+f (θ 0−θ i , j )+. .. .. i=1 ChemQuest
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  23. 23. Drug Discovery 1990sThe instruction came down from on high todevelop combinatorial chemistryThis idea arose from protein chemistry: Protein sequencers Ala-Met-Pro-Ala-Arg................ Protein synthesis by the opposite processA company might make 5000 compounds in ayear.Combinatorial libraries ~ 104 to 106 ChemQuest
  24. 24. Testing had to Change Too!Biological testing by this time was highlyspecialised in pharmacology (animals) andbiochemistry (tissues, cells & cultures) labsDesigned to cope with a work load in the1000s per annumLed to the development of ingeniousautomation and, most importantly,miniaturisation ChemQuest
  25. 25. Combinatorial chemistryAn internet query -‘What is combinatorial chemistry?’and a reply -‘A method of increasing the size of thehaystack in which you find a needle.’ **C. D. Floyd et al. (1996). Chemistry in Britain, March, pp.31-5. ChemQuest
  26. 26. Combinatorial chemistry Do libraries need to be designed? R2 R1 N R3 R4 300 R1, 800 R2, 500 R3, and 750 R4 gives a total of 9.0 x 1010 compounds.At 50,000 compounds per week it would take 34 thousand years to test them all ChemQuest
  27. 27. Has Combi. Chem. Delivered?Sadly, noIf a company has 10 tests which cost $1 percompound to test......Increasing the supply from 5,000 a year to amillion.............Puts up costs from $50,000 to $10 million!! ChemQuest
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  29. 29. Average Cost is $6.2 billion ChemQuest
  30. 30. Source of Drugs TodayA 2006 review claimed that 28% of NCEslaunched on to the market between 1981 and2002 were natural products or derived fromnatural products.A further 24% were said to have been basedon mimics of pharmacophores related tonatural products.Thus, 52% of new drugs from natureOnly 1 new drug from comb chem in 20years ChemQuest
  31. 31. Genomics ChemQuest
  32. 32. Impact of HG DiscoveryPotentially provided 1000s of new targets fordrug design, but ! A gene codes for a protein but we still need the structure of the protein Genes turn on and off according to the needs of the cells and effect of other genes/proteinsPotential to characterise a “cause” for sideeffectsPersonalised medicine ChemQuest
  33. 33. Personalised MedicineAny new drug will, at most, have only beengiven to a few thousand peopleSide effects only appear gradually as thewhole genome is exploredFuture drug discovery and dispensing may bebased on specific genetic sub-populations ChemQuest
  34. 34. ChemQuest

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