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Lecture 7


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Lecture 7

  1. 1. Medicinal Chemistry Lecture 7
  2. 2. Midterm Exam Outline <ul><li>50 questions </li></ul><ul><li>10% of the overall class grade </li></ul><ul><li>Question types: </li></ul><ul><li>Multiple choice questions </li></ul><ul><li>True or false </li></ul><ul><li>Fill in the blanks </li></ul><ul><li>Short answers </li></ul>
  3. 3. <ul><li>Receptors and Receptor Sites </li></ul>
  4. 4. What is receptor, receptor site? <ul><li>A receptor is a biological molecule that yield a biological response upon interaction with a drug molecule </li></ul>
  5. 5. Classes of Receptors <ul><li>Lipoproteins or glycoproteins: </li></ul><ul><li>The most common form of receptors </li></ul><ul><li>Often, firmly embedded in cell membrane or cell-organelle membrane </li></ul><ul><li>Their isolation may lead to structure collapse </li></ul><ul><li>2. Pure proteins: </li></ul><ul><li>Frequent drug receptors (e.g. enzymes) </li></ul>
  6. 6. Continue… <ul><li>3. Nucleic acids: </li></ul><ul><li>Important category of drug receptors </li></ul><ul><li>Targeted by antibiotics, antitumor agents, and steroid hormones (occasionally) </li></ul><ul><li>4. Lipids </li></ul><ul><li>Occasionally regarded as drug targets </li></ul>
  7. 7. What is a druggable target? <ul><li>A macromolecule that is intimately connected with a disease process but is not crucial to a wide range of normal biochemical processes </li></ul>
  8. 8. Molecular Recognition <ul><li>Bonding forces between ligands and receptors: </li></ul><ul><li>Covalent Bonding </li></ul><ul><li>Ionic Bonding </li></ul><ul><li>Dipole-Dipole Interactions (that include: hydrogen bonding, charge transfer bonding, hydrophobic bonding, and Van der Waal’s forces). </li></ul>
  9. 9. Covalent Bonding <ul><li>Not very common </li></ul><ul><li>Not very desirable (with few exceptions) </li></ul><ul><li>Strongest bonding </li></ul><ul><li>Irreversible </li></ul><ul><li>Found in cancer chemotherapy and in the inhibition of certain enzymes (rare otherwise) </li></ul>
  10. 10. Ionic Bonding <ul><li>Important because many of the functional groups will be in the ionized form at the physiological pH. </li></ul><ul><li>Usually Reversible </li></ul><ul><li>Ubiquitous </li></ul><ul><li>Effective at greater distances when compared to the other bonding types </li></ul>
  11. 11. Hydrogen Bonding <ul><li>Considerable importance in stabilizing structures by intramolecular bond formation </li></ul><ul><li>Not as important in intermolecular bonding in aqueous solutions. Why? </li></ul><ul><li>Based on electrostatic interaction between the nonbonding electron pair of a heteroatom (e.g. O, N, and S) as the donor, and the electron deficient hydrogen atom that is chemically bonded to a more electronegative atom (e.g. SH, NH, and OH). </li></ul><ul><li>Weak interaction </li></ul>
  12. 12. Charge Transfer Interaction (CT) <ul><li>Important in drug receptor interactions </li></ul><ul><li>Especially important in the interaction of antimalarials and their receptors and in the intercalation of some antibiotics with DNA </li></ul>
  13. 14. Dispersion and Van der Waal’s Interactions <ul><li>Based on polarizability </li></ul><ul><li>Ion-dipole attractive forces, dipole-dipole interactions are weaker bonds (in comparison the covalent and ionic bonds) </li></ul><ul><li>Important because of their large numbers between drugs and receptors </li></ul>
  14. 15. Hydrophobic Interactions <ul><li>Play an important role in: </li></ul><ul><li>Stabilizing the conformations of proteins </li></ul><ul><li>Transport of lipids by plasma membranes </li></ul><ul><li>Binding of steroids to their receptors </li></ul><ul><li>Also explains the low solubility of hydrocarbons in water. How? </li></ul>
  15. 20. Definitions of Classical Binding Terms for Drug-Receptor Interactions <ul><li>Agonist: </li></ul><ul><li>Substance that interact with a specific cellular constituent, the receptor, and elicit an observable biological response. </li></ul><ul><li>May be endogenous (e.g. hormone) or exogenous (e. g synthetic drug). </li></ul>
  16. 26. Continue… <ul><li>2. Partial Agonists: </li></ul><ul><li>Act on the same messenger as other agonists in a group of ligands. </li></ul><ul><li>Regardless of their dose, they can not produce the same maximal biological response as the full agonist </li></ul><ul><li>Intrinsic Activity: </li></ul><ul><li>Proportionality constant of the ability of the agonist to activate the receptor as compared to the maximally active compound in the series being studied. </li></ul><ul><li>Has a maximum value of unity for full agonists and a minimum value of zero for antagonists. </li></ul>
  17. 27. Continue… <ul><li>3. Antagonists: </li></ul><ul><li>Inhibits the effect of an antagonist but has no biological activity of its own in that particular system. </li></ul>
  18. 28. <ul><li>I. Antagonists Acting at the Binding Site: </li></ul>
  19. 29. II. Antagonists acting indirectly on the binding site
  20. 30. Antagonism by umbrella effect
  21. 31. <ul><li>4. Inverse Agonists: </li></ul><ul><li>Also known as negative antagonists </li></ul><ul><li>Inverse agonist act at the same receptor as an agonist yet produces an opposite effect </li></ul><ul><li>Distinction between antagonists and inverse agonists is important. </li></ul>
  22. 32. <ul><li>The End </li></ul>