Pharmaceutical Analysis Lecture 1

Pharmaceutical Analysis - Lecture 1: Intermolecular Interactions

• This lecture covers intermolecular interactions, crucial for understanding drug action, metabolism, and interactions with other molecules.
• Recommended texts for further study include "An Introduction to Medicinal Chemistry" by Graham L. Patrick (2017, 2013, 2009) and "The Organic Chemistry of Drug Design and Drug Action" by Richard B. Silverman & Mark W. Holladay (2013).
• Learning objectives include understanding why and how molecules interact, recognizing non-covalent interactions, measuring intermolecular interaction strengths, and applying this knowledge to drug and medicine contexts.
• Intermolecular interactions are key to understanding biological macromolecules, drug mechanisms, drug metabolism, and drug/excipient interactions.

DNA Secondary Structure

• DNA's structure is crucial for its functionality.
• Nitrogenous bases (adenine, thymine, guanine, cytosine) pair in specific ways.
• Base pairing forms a double helix with a sugar-phosphate backbone.
• The structure has major and minor grooves, which play a role in interactions with other molecules. Figures showing the structure of DNA are in the notes.

Protein Secondary Structures

• Alpha-helix: Components are amino acid residues linked via hydrogen bonding, forming a spiral shape. Figure illustrating the alpha helix structure is in the notes; features dimensions.
• Beta-sheet: Hydrogen bonds connect polypeptide chains, forming a pleated sheet shape. Figure illustrating the beta sheet structure is in the notes; the structure of anti-parallel and parallel are shown.

Protein Tertiary Structures

• Tertiary structure is formed through attractions between alpha-helices, beta-sheets, and elements of secondary structure.
• These attractions include hydrophobic interactions, electrostatic attraction, and metal ion coordination. Figure with an example of how tertiary structures form is in the notes; shows the different types of interactions.

Enzyme Function

• Enzymes, typically proteins, speed up biochemical reactions.
• The substrate (S) binds to the enzyme's active site (E) forming a complex.
• The enzyme then catalyzes the conversion of the substrate into product (P).
• The reaction proceeds to release the product, and the enzyme is regenerated. Figure of enzyme action is in the notes.

Supramolecular Chemistry

• This is the study of systems of molecules or ions that are held together by non-covalent interactions.
• Examples of interactions include electrostatic effects, ion-dipole/dipole-dipole interactions, hydrogen bonding, charge-transfer interactions, π-π interactions, cation-π interactions, halogen bonds, and London dispersion/van der Waals forces. The specific interactions are described in detail in the notes.

Covalent Bonding

• Covalent bonds involve the sharing of electron pairs between atoms.
• They are strong, directional bonds.
• Their strength, and the distance between atoms, are dependent on the atoms involved in the bond. Table summarising data on bonds is in the notes.

Ionic Interactions

• Ionic interactions are attractions between ions with opposite charges.
• These interactions are crucial in protein structures, physiological pH.
• Positively charged side chains (Arginine, Lysine, Histidine) interact with negatively charged side chains (Aspartic acid, Glutamic acid). Figure of ionic interactions in proteins is in the notes, and examples of structures are included.
• Their strength is proportional to 1/r^2, where r is the distance between the charges. Important figure of ionic interactions in the notes.

Ion-dipole/Dipole-dipole Interactions

• These interactions occur between ions and polar molecules, and between polar molecules.
• Strength varies, depending ion/molecule strength.
• Key to understanding how molecules interact. Examples of ion-dipole interactions are shown in the notes.
• Strength varies from 5 to 50kJ/mol.

Hydrogen Bonding

• Hydrogen bonding is a strong type of dipole-dipole interaction.
• Essential for water, proteins, and DNA structures.
• Typical strengths are 4 to 120 kJ/mol, which vary based on environment.
• Very directional with a short interaction distance. Examples of donors and acceptors are provided.
• Often intramolecular and can affect structure by masking pharmacophoric groups and creating biosteric structure.

Charge Transfer Complexes

• These result from electron transfer between a good electron donor and acceptor molecule.
• Strength is proportional to the difference in the ionization potentials of the molecules; varies from 5 kJ/mol to 35 kJ/mol.
• Relevant for drug-receptor interaction. Notes include diagrams of examples.

Hydrophobic Interactions

• Water preferentially interacts with itself, leading to the exclusion of nonpolar molecules.
• Nonpolar molecules aggregate to minimize contact with water. Note the different types of aggregates are included.
• Critical in protein folding and membrane formation. The different types of liposomes are also included.

π-π Interactions

• These are attractions between aromatic rings.
• A type of hydrophobic interaction.
• Important in protein structures and determining drug intercalation of DNA.The different configurations noted as edge to face and sandwich are shown with the different examples.

Cation-π Interactions

• Cationic groups on drugs can interact with the π-system of protein molecules in receptors.
• Relatively strong- 5 to 25 kJ/mol.
• This interaction is vital in drug design. The notes include diagrams demonstrating cation-π interactions.

Halogen Bonding

• A form of dipole-dipole interaction between halogen and donor elements (such as nitrogen, oxygen and sulfur).
• 5 to 60kJ/mol.
• Involved in drug-receptor interactions; examples included demonstrating halogen bonding.

London Dispersion Forces/van der Waals Interactions

• Weak attractive forces occurring between all molecules.
• Result from temporary fluctuations in electron distribution around atoms.
• Important for both molecules in aqueous and non-aqueous solutions.
• Can influence drug-receptor binding.

Cooperativity

• Several weak interactions can combine to create stronger overall interactions.
• The loss of translational energy means decreased entropy during subsequent interactions.
• Critical for many molecular functions including drug-receptor binding (in the example of dibucaine) and other cellular processes.

Determining Interaction Strengths

• Various methods for quantifying interactions, including spectroscopy, displacement methods, and isothermal titration calorimetry (ITC).