PHRD5915 Drug Design Lecture 6 - Prodrugs II

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  1. 3 components of active site triad
    • 1) Asp
    • 2) His
    • 3) Ser
  2. role of histidine in the active site triad
    with the help of Asp, deprotonates serine hydroxyl
  3. role of serine in the active site triad
    • (after deprotonation by His) nucleophilic attack on substrate carbonyl cationĀ 
    • oxyanion hole stabilizes tetrahedral transition state
  4. role of aspartate in the active site triad
    aids histidine in deprotonation of serine
  5. mechanism of cysteine proteases
    use strong nucleophile & forms covalent enzyme-substrate complex
  6. mechanism of aspartyl protease
    • contains 2 Asp residues that act in general acid-base mech
    • activate water molecule between Asp's to serve as nucleophile
  7. mechanism of metalloproteases
    use coordinated metal (often Zn), 2-3 His, & acidic side chain to activate water
  8. where first protonation occurs in Prilosec
    @ pyrimidine
  9. where second protonation occurs in Prilosec
    N of benzimidazole (double ring system w/ higher pKa)
  10. how Prilosec binds to proton pump
    cysteine residues on the parietal cell acid pump alkylate the sulfenamide electrophile of Prilosec, forming a disulfide covalent bond
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PHRD5915 Drug Design Lecture 6 - Prodrugs II
2014-03-14 10:15:06

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