Intermolecular Forces and Biological Systems

### Intermolecular Forces

• London Dispersion forces become more important for larger molecules.
• Hydrogen bonding is present in molecules containing -OH or -NH groups, as well as HF molecules.

The Body's Systems

• The nervous system (CNS) includes the sympathetic and parasympathetic nervous systems and uses polarization-depolarization signals.
• The liver is responsible for detoxification and storage.
• Understanding hormones requires an understanding of the molecular level of body organization.

Drug Targets

• Macromolecules such as proteins, lipids, carbohydrates, and nucleic acids are common drug targets.
• Drug action occurs through binding to these molecules.
• The binding site is a specific region on a macromolecule where the interaction occurs.
• Drug-target interactions can be permanent (irreversible) through covalent bonding or reversible through other types of interactions.

Binding Mechanisms

• Binding occurs through functional groups on a chemical compound.
• Functional groups utilize their electronic and shape characteristics for binding.
• Bonds can be intermolecular or intramolecular.
• Reversible binding involves an equilibrium between the drug and its target.

Receptor-Drug Interaction

• Receptors are often membrane-bound proteins that bind to ligands, triggering physiological responses.
• Receptors are difficult to isolate due to their small amounts and challenging purification.
• Signal transduction occurs through receptor binding, resulting in a biological response.
• The driving force for drug-receptor interaction is the low energy state of the complex.
• Biological activity is related to the drug's affinity for the receptor and the stability of the complex.
• The dissociation constant of the drug-receptor complex reflects the drug's potency.

Types of Bonds in Receptor-Drug Interaction

• Covalent bonds: Strong and irreversible, rare in drug-receptor interactions but more common in drug-enzyme and drug-DNA interactions.
  • Nucleophiles in biological systems include thiol (cysteine), hydroxyl (serine), amine (lysine), and carboxylate (glutamic acid).
  • Electrophiles include epoxide rings, alkyl groups bonded to halogens, and positively charged centers.
• Ionic or electrostatic interactions: Weaker than covalent bonds, prevalent in drug-receptor interaction.
  • Opposite charges between drug and receptor molecules are required.
  • Ionization and distance between charges influence bond strength.
  • Examples include interactions between acidic amino acids (aspartic acid, glutamic acid) and basic amino acids (histidine, lysine, arginine).
• Ion-dipole and dipole-dipole interactions: Occur when ionic groups interact with permanent dipoles.
  • Energy level is between -1 to -7 kcal/mol.
  • Ion-dipole interactions are stronger than dipole-dipole interactions.
• Hydrogen bonding: Requires both a hydrogen bond donor (electron-deficient hydrogen) and acceptor (electron-rich atom).
  • Bond strength is -1 to -7 kcal/mol.
  • H-bonds are typically between 1.5-2.2 Å.
  • Anions are better H-bond acceptors than uncharged compounds.
  • Delocalized lone pairs on nitrogen weaken H-bond donor capacity.
  • Two types: Intramolecular (within a molecule) and intermolecular (between molecules).
  • Intramolecular H-bonding can influence pharmacological action.
• Charge-transfer interactions: Occur between electron donor and acceptor groups.
  • Electron donors include alkenes, alkynes, aromatic rings with electron-donating groups, and atoms with non-bonded electron pairs (O, N, S).
  • Electron acceptors include aromatic rings with electron-withdrawing groups.
  • Examples include aromatic rings of tyrosine and carboxylate groups of aspartate (donors) and cysteine (acceptor).
• Hydrophobic interactions: Occur between nonpolar groups surrounded by ordered water molecules.
  • Water molecules become disordered when nonpolar groups interact, increasing entropy and stabilizing the complex.
  • This stabilization is called hydrophobic interaction.
  • Examples include π-π interactions between aromatic rings in face-to-face arrangements.
• Van der Waals forces: Temporary dipole interactions due to non-symmetrical electron distribution.
  • These bonds are weak with a stability of -0.5 kcal/mol.

Drug-Receptor Interactions Examples

• Dibucaine, a local anesthetic drug, exhibits various types of interactions.

Receptor Agonists and Antagonists

• Agonists: Mimic natural messengers, binding reversibly to the receptor and activating it.
• Antagonists: Block the action of natural messengers or agonists by binding to the receptor.
  • Strategies for antagonist design:
    • Designed to fit the binding site but fail to change the receptor's shape.
    • Allosteric antagonists bind to different sites on the receptor.
    • "Umbrella effect" antagonists bind near the binding site, preventing the messenger's access.

Competitive vs. Non-Competitive Antagonists

• Competitive antagonists: Compete with agonists for receptor binding, reducing agonism and requiring higher agonist concentrations.
• Non-competitive antagonists: Bind to different sites on the receptor, either preventing agonist binding or the agonistic effect, reducing the maximum achievable response.

Affinity, Efficacy, and Potency

• Affinity: The strength of drug binding to the receptor.
• Efficacy: The maximum biological effect a drug can produce.
• Potency: The amount of drug needed to achieve a defined biological effect.
• High affinity does not guarantee high efficacy.
• Potency is influenced by affinity and the efficiency of coupling drug-receptor interactions to response.

Recommended Books

• The Organic Chemistry of Drug Design by Richard B. Silverman (2nd Edition)
• An Introduction to Medicinal Chemistry by Graham L. Patrick (4th Edition)