2025-MD1010-BiologicalChemistry-Lectures-Part2(1)

Week 2 Overview

  • Focus on proteins and acid-base chemistry regarding drugs and biomolecules.

  • Presented by Assoc. Prof. Mike Liddell.

Acid-Base Properties of Drugs/Biomolecules

Learning Outcomes

  • Understand the significance of pH and how it can be manipulated within biological systems.

  • Determine the ionization of functional groups and correlate it to drug absorption.

  • Assess drug incompatibilities, notably with antacids.

Key Terms

  • Chemotherapeutic

  • β-lactam

  • Enzyme inhibitor: reversible & irreversible inhibition

  • Prodrug

  • Conjugate acid/base

  • pH buffer (e.g., bicarbonate, phosphate)

  • Ionization, pH vs. pKa

  • Antacids

  • Zwitterion

  • Isoelectric point.

Common Functional Groups in Organic Chemistry

  • Alkyl (alkoxy)

  • Amines: classified as primary, secondary, or tertiary based on hydrogen attachment to nitrogen.

  • Aromatic compounds (arene): benzene rings and derivatives.

  • Alcohols (hydroxyl functional group)

  • Ethers

  • Carboxylic acids and esters

  • Amides (primary, secondary, tertiary based on H attachment).

Fischer Projections

For Amino Acids

  • Utilizes chiral centers for configuration.

  • Horizontal bonds project towards the viewer, vertical bonds point away.

  • Highest oxidize at the top, side chain (-R) at the bottom.

  • L and D configurations are based on the position of the amino group.

For Monosaccharides

  • C2 is the chiral center.

  • Configuration of sugars related to D-glyceraldehyde.

  • Most natural sugars exist in D-configuration.

Drug Binding

Crucial for Drug Interaction

  • The 3D shape of a drug is essential for fitting into enzyme or receptor sites.

  • Polarization of functional groups enhances bonding interactions, aligning with the 'lock and key' hypothesis.

Proteins

Definitions

  • Amino Acid (AA): a small building block consisting of a carboxyl group and amino group.

  • Protein: a macromolecular polymer formed by peptide bonds linking >30 AAs, varying from 15 to 1000 kDa in molecular weight.

  • Classification based on structure: globular proteins.

Enzymes

  • Proteins that catalyze virtually all reactions in living organisms.

  • Active sites allow substrates to bind and proceed with chemical reactions.

  • Intermolecular forces through amino acids at the active site are essential for substrate binding.

Importance of Shape in Drug Targets

  • 3D shape of enzymes is critical for biological function.

  • Example: Drugs binding to HIV-1 Protease as reversible competitive inhibitors.

Drug Targets and Inhibition

Types of Inhibition

  • Reversible Inhibition: Temporary binding via non-covalent bonds.

  • Irreversible Inhibition: Permanent blockage by covalent bonding.

Modes of Reversible Inhibition

  • Ionic Bonds: Between oppositely charged groups (e.g., A- and B+).

  • Hydrogen Bonds: Formed between hydrogen bond donor and acceptor groups.

  • Van der Waals Interactions: Occur between hydrocarbon regions, relying on transient fluctuations in electron density.

Irreversible Inhibition and Toxicity

  • Irreversible inhibitors can be very toxic but may have long-lasting effects.

  • Chemotherapeutic agents aim to selectively target pathogens while minimizing toxicity to the host.

Examples of Drugs

Penicillins

  • β-Lactam drugs targeting bacterial cell wall synthesis.

Other Drugs

  • Morphine, Oseltamivir (Tamiflu), Enalapril

  • Consider pro-drug factors affecting bioavailability.

Prodrugs

  • Inactive compounds converted to active drugs in the body, optimizing absorption and decreasing toxicity.

  • Must ensure non-toxic groups are removed during conversion.

pH Effects on Drugs

Routes of Entry and Environment

  • Drug pH influences ionization, impacting absorption (e.g., stomach vs. intestine).

  • Key pH levels: Stomach (1-4), Intestine (8-9), Blood (7.4).

Acid-Base Chemistry Parameters

Acids and Bases

  • Ka: Acid dissociation constant

  • pKa: Negative log of Ka; strong acids dissociate completely.

  • Weak Acid/Base Definition: Partial dissociation characteristic of common drugs.

Physiological pH

  • Maintained by buffer systems in the body, crucial for stable biochemical environments.

  • Examples of common solutions and their pH ranges.

Blood Buffers

  • Bicarbonate, phosphate, and protein buffering systems regulate physiological pH.

Drug Properties and Distribution

  • Understand how drugs' acidic or basic nature influences their state in different pH environments.

  • Determine the implications of drug ionization for absorption and distribution.

Case Studies

Ibuprofen and Atomoxetine

  • Analyze how pH and functional groups influence absorption and distribution.

Conclusion

  • Recognize the critical relationship between drug chemistry, pH, ionization, and physiological conditions affecting drug efficacy. End of Week 2.