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Medicinal chemistry Basics


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Medicinal chemistry, Drug Discovery Introduction
by Graham L. Patrick

Published in: Science
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Medicinal chemistry Basics

  1. 1. Med Medicinal/Ph armaceutical Chemistry Biological Medical Pharmaceutical Science What is Medicinal/Pharmaceutical Chemistry ? Chem
  2. 2. HISTORY OF MEDICINAL CHEMISTRY Medicinal chemistry received formal recognition in academic pharmacy in 1932 Ehrlich’s “Side chain theory” and chemotherapy and Fischer’s lock-and key theory Birth of Modern Med Chem 1800 Synthesis of Urea 1828 started Organic medicinal Chemistry Emperor Frederick II issued the Magna Carta of pharmacy in 1240 1500 BC Egyptian papyrus ebers 700 drugs originated from animal/plants/minerals 2000 BC Materia Medica 250 vegetables drug And 120 mineral drugs Med Chem
  3. 3. What is DrugMed Chem  No drug is totally safe. Drugs vary in the side effects they might have.  The dose level of a compound determines whether it will act a medicine or as a poison.  The therapeutic index is a measure of a drugs beneficial effect at a low dose versus its harmful effects at higher dose. A high therapeutic index indicates a large safety margin between beneficial and toxic doses  The principle of selective toxicity means that useful drugs show toxicity against foreign or abnormal cells but not against normal host cell why, where, how drug act ?  Drug : Any substance which generate biological response. Good or Bad drugs
  4. 4. Drug TargetMed Chem Why should chemicals, some of which have remarkably simple structures, have such an important effect on such a complicated and large structure as a human being ? Cytoplasm Nucleus Nuclear membrane Cell membrane
  5. 5. Chemical Structure of Cell wallMed Chem Glycoprotein Lipid bilayer phosphatidylcholine, phosphatidylethanolamine, phosphatidylserine, and phosphatidylinositol
  6. 6. Chemical Structure of Cell wallMed Chem Glycoprotein O-aglycon N-aglycon Glycophorin
  7. 7. Drug targets at the molecular levelMed Chem Proteins : Enzymes Receptors Transport proteins Nucleic Acids : DNA RNA Biological 10% Receptor Agonist 12% Receptor Antagonist 24% Ion Channel Modulator 8% Enzyme Inhibitor 38% Misc 8%
  8. 8. Drug targets at the molecular levelMed Chem The equilibrium of a drug being bound and unbound to its target.
  9. 9. Intermolecular bonding forcesMed Chem Electrostatic or ionic bonds Hydrogen bonds Van der Waals interactions Dipole-Dipole and ion-Dipole interactions Repulsive interactions The role of water and hydrophobic interactions Electrostatic or ionic bonds Hydrogen bondsCovalent bonds Van der Waals interactions 1.5–2.2 Å1.0–1.5 Å
  10. 10. Med ChemElectrostatic or ionic bonds An ionic or electrostatic bond is the strongest of the intermolecular bonds Closer the charged atoms stronger the bond Strength of bond depend on environment Most important initial interaction as the drug enters the binding site
  11. 11. Hydrogen bondsMed Chem (X, Y = oxygen or nitrogen; HBD = hydrogen bond donor, HBA = hydrogen bond acceptor) For H bond require an electron-rich hetero- atom (With lone pair) and an electron-deficient hydrogen The hydrogen bond (5 to 30 kJ/mole) is stronger than a van der Waals interaction, but weaker than covalent or ionic bonds. hydrogen bond donor (HBD) Has covalently bonded electro +Ve H hydrogen bond acceptor (HBA) provide electro –Ve atom hydrogen bond flip-flop
  12. 12. Hydrogen bondsMed Chem
  13. 13. Hydrogen bondsMed Chem Orbital overlap in a hydrogen bond. Weak form of sigma bonding Bond angel 130-180  moderated bond strength 90  bond angel week bond Optimum orientation is where bond angel is 180  where it is strongest  bond
  14. 14. Hydrogen bond donor (HBD)/acceptor (HBA)Med Chem R-F Fluorine is highly electronegative atom With 3 lone pair of electron…. But still weak HBA ?????
  15. 15. Van der Waals interactionsMed Chem
  16. 16. Med ChemDipole-dipole
  17. 17. Med ChemIon-dipole interactions
  18. 18. Repulsive interactionsMed Chem Induced dipole interaction between an alkyl ammonium ion and an aromatic ring. Nicotinic acetylcholine receptor tryptophan residue
  19. 19. Repulsive interactionsMed Chem Important to keep molecule at specific distance. If molecules come too close there molecular orbitals start to overlap and this results in repulsion. Same group try to repel each other…For example, two charged groups of identical charge are repelled.
  20. 20. The role of water and hydrophobic interactionsMed Chem Ritonavir
  21. 21. The role of water Hydrophobic interactions.Med Chem
  22. 22. Pharmacokinetic issues and medicinesMed Chem Pharmacodynamics is the study of how a drug binds to its target binding site and produces a pharmacological effect The study of how a drug is absorbed, distributed, metabolized, and excreted (known as ADME in the pharmaceutical industry) is called pharmacokinetics. ‘what the body does to the drug’ ‘what the drug does to the body’
  23. 23. Classification of drugsMed Chem Pharmacological effect analgesics, antipsychotics, antihypertensive, anti-asthmatics, and antibiotics Chemical structure penicillin's, barbiturates, opiates, steroids, and catecholamine's ephalosporins, sulphonamides, opioids, and glucocorticoids target system target molecule anticholinesterases are drugs which act by inhibiting the enzyme acetylcholinesterase neurotransmitter
  24. 24. Naming of drugs and medicinesMed Chem Ro31-8959, ABT-538, and MK-639 were compounds prepared by Roche, Abbott, and Merck Promising anti-HIV drugs and were named saquinavir, ritonavir , and indinavir In market brand name (proprietary) Fortovase ®, Norvir ® and Crixivan Different formulation has different brand name For generic (non-proprietary) Recommended International Nonproprietary Name (rINN), which is usually identical To the name Of The drug.
  25. 25. Protein Structure and function of proteinsMed Chem The 20 common amino acids found in humans
  26. 26. Primary Structure of proteinsMed Chem Met-encephalin (one of the body’s own painkillers) The primary structure is the order in which the individual amino acids making up the protein are linked together through peptide bonds
  27. 27. The secondary structure of proteinsMed Chem The secondary structure of proteins consists of regions of ordered structure adopted by the protein chain. The -helix The -pleated sheet (antiparallel arrangement)
  28. 28. The secondary structure of proteinsMed Chem Hydrogen bonding in antiparallel and parallel ß-sheets (the arrows are pointing to the C –terminal end of the chain) The -turn showing hydrogen bonding between the first and third peptide bond.
  29. 29. The tertiary structure of proteinsMed Chem Human cyclindependent kinase 2 (CDK2), where cylinders represent -helices and arrows represent ß-sheets.
  30. 30. The tertiary structure of proteinsMed Chem Tertiary structure formation as a result of intramolecular interactions. With the exception of disulphide bonds, the bonding interactions involved in tertiary structure are the same as the intermolecular bonds
  31. 31. The tertiary structure of proteinsMed Chem Covalent bonds-disulphides links Ionic or electrostatic bonds Hydrogen bonds Van der Waals and hydrophobic interactions
  32. 32. The quartarnary structure of proteinsMed Chem Only proteins that are made up of a number of protein subunits have quaternary structure.