Cell Biology and Drug Interaction Overview

Drugs and Drug Targets Overview

• Drugs are compounds that interact with biological systems to produce a biological response.
• No drug is completely safe; side effects vary.
• Dose level determines whether a compound acts as a medicine or a poison.

Cell Structure

• Cells are the basic building blocks of life, the smallest living units of an organism.
• Cells grow, reproduce, use energy, adapt, and respond to their environment.
• A cell can be an entire organism (bacteria, protists, yeasts) or one of billions in an organism.
• Cells are either prokaryotic or eukaryotic.

Cell Structure (Eukaryotes)

• Human, animal, and plant cells are eukaryotic cells.
• The nucleus contains the genetic blueprint (DNA).
• Cytoplasm is the fluid within the cell.
• Organelles are structures within the cell.
• Mitochondria produce energy.
• Ribosomes are the cell's protein factories.

Cell Membrane

• The cell membrane is a phospholipid bilayer.
• Hydrophobic tails interact with each other, hidden from water.
• Polar head groups interact with water on both sides of the membrane.
• The cell membrane provides a hydrophobic barrier, preventing the passage of water and polar molecules.
• Proteins are present within the membrane, some acting as ion channels and carrier proteins.
• Diagram shows exterior with high sodium and interior with high potassium.

Drug Targets

• Drugs act on molecular targets within cells, often in the cell membrane.
• Drug targets are larger (macromolecules) than drugs.
• Drugs interact with targets by binding to binding sites, typically hydrophobic pockets on the surface of the target molecule.

Binding Interactions

• Binding interactions often result in an induced fit.
• Binding site changes shape to accommodate the drug.
• Induced fit may alter the overall shape of drug or target.
• Critical to the pharmacological effect of the drug.
• Induced fit model describes a ligand (drug, substrate) binding to a protein (enzyme or receptor) causing the protein to change shape to accommodate the ligand better.

Pharmacodynamics

• Pharmacodynamics is the study of how drugs interact with their targets and produce a pharmacological effect.

Intermolecular Bonding Forces - Electrostatic/Ionic Bonds

• Strongest intermolecular bonds (20-40 kJ mol⁻¹).
• Between groups of opposite charge.
• Strength is inversely proportional to the distance between charged groups.
• Stronger in hydrophobic environments.
• Initial interactions as a drug enters a binding site.

Intermolecular Bonding Forces - Hydrogen Bonds

• Variable strength; weaker than electrostatic but stronger than van der Waals interactions.
• Between electron-deficient hydrogen and electron-rich heteroatom (N or O).
• Electron-deficient hydrogen is a hydrogen bond donor.
• Electron-rich heteroatom is a hydrogen bond acceptor.
• Involves orbitals, directional, optimum orientation angle of 180°.

Intermolecular Bonding Forces - Van der Waals Interactions (London Forces)

• Very weak interactions (2-4 kJ mol⁻¹).
• Between hydrophobic regions of the drug and target, due to transient areas of high/low electron density leading to temporary dipoles.
• Interactions drop off rapidly with distance.
• Must be close to binding region for interactions to occur.
• Crucial to binding (e.g., amphotericin B).

Intermolecular Bonding Forces - Dipole-Dipole Interactions

• Occur if drug and binding site have dipole moments.
• Dipoles align with each other as the drug enters the binding site.
• Beneficial if binding groups correctly positioned.
• Detrimental if incorrect positioning.
• Interaction strength decreases with distance, quicker than electrostatic interactions but slower than van der Waals interactions.

Intermolecular Bonding Forces - Ion-Dipole Interactions

• Occur where the charge of one molecule interacts with the dipole moment of another.
• Stronger than dipole-dipole interactions.
• Interaction strength doesn't decrease rapidly with distance compared to dipole-dipole interactions.

Intermolecular Bonding Forces - Induced Dipole Interactions

• Occur when the charge on one molecule induces a dipole in another.
• Occurs between a quaternary ammonium ion and an aromatic ring.

Desolvation Penalties

• Polar regions of a drug and its target are solvated before interaction.
• Desolvation is needed and requires energy.
• Energy gained from drug-target interactions must be greater than the desolvation energy needed.

Hydrophobic Interactions

• Hydrophobic regions of the drug and its target are not solvated.
• Water molecules interact and form an ordered layer around hydrophobic regions.
• The ordered layer around hydrophobic areas is negative entropy.
• Interactions liberate/free up ordered water molecules.
• Results in increase in entropy, beneficial to binding energy.

Drug Targets - Cell Membrane Lipids

• Drugs act on cell membrane lipids (e.g., anaesthetics, some antibiotics).
• Targets phospholipid bilayer.
• Amphotericin B is an antifungal agent that makes tunnels in membranes, draining the cell.
• Diagram presents the structure and action of Amphotericin B.

Drug Targets - Carbohydrates

• Present on cell surfaces often attached to proteins/lipids (forming glycoproteins/glycolipids.
• Important for cell recognition, regulation, growth.
• Potential targets for treating bacterial/viral infection, cancer, and autoimmune disease.
• Carbohydrates act as antigens.
• Several drugs are carbohydrates or contain carbohydrates in their structure (e.g., streptomycin, zidovudine, acyclovir).
• Carbohydrates are more challenging to synthesize compared to peptides, but offer potential for novel structures.

Additional Notes

• Clinically useful drugs commonly have trade names.
• Many structures produced during development aren't considered for clinical use.
• Structures are sometimes identified by specific codes by research groups.
• Glycolipids and glycoproteins are integral membrane proteins that have carbohydrate chains covalently attached and are exposed on the outer surface of the cell.
• Glycolipids have a hydrophobic tail, allowing them to be embedded in the cell membrane’s lipid bilayer; they primarily act as markers for cellular recognition.
• Glycoproteins have a hydrophobic region that interacts with the hydrophobic portion of the cell membrane, assisting anchorages within the membrane. Glycoproteins have crucial roles in cell-cell recognition, protection, and immune response.