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Lecture 7


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