Chemistry in the Service of Mankind: Pre-Seminar Notes

Speaker

• Dr. John Wai (WuXi AppTec)

Pre-Requisite Knowledge

• Required Viewing: Seminar on Drug Discovery and Organic Chemistry
  • Key concepts:
    • Lead identification
    • Lead optimization
    • Mechanism of how Tamiflu prevents influenza virus spread

Seminar Context

• Builds on knowledge from the DSE curriculum in Chemistry and Combined Science (Chemistry)

HIV Overview

• HIV is a retrovirus, integrating its RNA genome into human DNA
• Untreated HIV can lead to AIDS
• Goal of scientists: Design a drug to minimize HIV replication

Drug Discovery: Raltegravir

• Raltegravir's Function: Inhibits HIV integrase enzyme, preventing viral genome insertion into human DNA
• Integrase Role: Facilitates integration of viral DNA into host genome

Drug Inhibition and Potency

• Inhibitors: Drugs that inhibit enzyme actions
  • Raltegravir is an integrase inhibitor
• Potency Metrics:
  • IC50: Concentration for 50% inhibition in vitro
  • IC95: Concentration for 95% inhibition in vitro
  • Lower IC values indicate higher potency

Acid/Base Properties in Drugs

• Drug molecules classified as acids or bases
• Acids:
  • HA (aq) + H₂O (l) → A⁻ (aq) + H₃O⁺ (aq)
  • Equilibrium constant for weak acids
• Bases:
  • B (aq) + H₂O (l) → HB⁺ (aq) + OH⁻ (aq)
  • Equilibrium constant for weak bases

pKa: Acid Strength Measure

• Definition: pKa = -log₁₀(Ka)
• Lower pKa = stronger acid; Higher pKa = weaker acid
• Examples:
  • Carboxylic acid in aspirin: pKa 3.49
  • Acetic acid: pKa 4.75
  • Ammonium: pKa 9.2

Protonation and Deprotonation

• Protonation: Addition of H⁺ ions
• Deprotonation: Removal of H⁺ ions
• Acids become deprotonated in a high pH environment if pKa < pH

Drug Delivery and Cell Membranes

• Protonation status affects drug's ability to cross cell membranes
• Negatively charged molecules (deprotonated acids) have difficulty crossing cell membranes
• Integrase inhibitor prototype is a weak organic acid

Seminar Coverage

• HIV infection mechanism
• Discovery of integrase inhibitor lead compound
• Solutions to optimization challenges in lead compound development

Glossary

• Hydrolysis
• Inhibitor
• Aspartic acid
• Glutamic acid
• Catalytic core
• Integrase
• Integration
• Pharmacophore
• DNA strand