BIOMD202 7p2 Introduction to Pharmaceutical Science and Stereochemistry

Introduction to Pharmaceutical Science and Drug Molecules

Speaker Profile - The speaker, Prabhat, is a pharmaceutical scientist by training. - Originally a pharmacist, though he never practiced in a pharmacy setting. - Academic and research focus is centered on drug delivery. - Drug delivery is defined as changing the chemical nature of an active drug of interest into various dosage forms, such as: - Tablets - Capsules - Injections - Gels - Transdermal patches - He has experience working in both the pharmaceutical industry and academia.
Defining a Drug Molecule - A recurring question in the field is: "What is a drug?" and "What kind of molecule is a drug?" - Comparison of molecules: - Oxygen: Not typically considered a drug in this context. - Carbon dioxide ( $CO_2$ ): Not typically considered a drug. - Paracetamol (Acetaminophen or Panadol): Yes, these are drugs. - The primary inquiry of the lecture is what defines "drug-like properties" in a molecule.

Fundamental Building Blocks of Drug Molecules

Molecular Basics
- A molecule is defined as a stable entity formed when two or more atoms of the same or different elements are bonded together.
- Examples provided: - Oxygen molecule ( $O_2$ ): Two atoms of oxygen.
- Water ( $H_2O$ ): Two atoms of hydrogen and one atom of oxygen.
- Not all molecules are drugs; a drug must have:
  - Sufficient pharmacological effect.
  - The ability to bind to an appropriate target site.
Building Blocks and Scaffold Structures
- Atoms: The fundamental units. Carbon acts as the primary scaffold element for most pharmaceutical drugs. - Chemical Bonds: Atoms are held together by single, double, or triple bonds. - Functional Groups: These are the active components within a molecule that act as reaction sites. For example, a carboxylic functional group allows a molecule to react with Sodium Hydroxide ( $NaOH$ ). - Molecular Geometry: The three-dimensional shape of the molecule. This is critical for drug-receptor recognition, following the "Lock and Key" principle of molecular binding.
Specificity and Receptors - Drugs generally bind to specific receptors to perform pharmacological activities (as previously discussed in lectures by Steve). - Example: Morphine is an opioid that binds specifically to opioid receptors (e.g., mu 1, mu 2, kappa). - Morphine typically will not bind to random receptors like GABA receptors because of its specificity.

Chemical Structure and Functional Groups: The Case of Ibuprofen

Overview of Ibuprofen - Ibuprofen is classified as a Non-Steroidal Anti-Inflammatory Drug (NSAID). - It is used for clinical indications like headaches or pain (e.g., after alcohol has cleared the body).
Structural Components of Ibuprofen - Benzene Ring (Phenyl Ring): A hexagonal structure consisting of six carbon atoms bonded with double bonds. This provides stability and is chemically inert. - Carboxylic Functional Group: This group imparts acidic properties to the molecule. Ibuprofen is, therefore, a weak acid. - Methyl Groups: The molecule contains methyl groups, with two projected on the left side of the structure.
Common Structural Motifs in Drugs - Heterocycles: Ring structures containing atoms other than carbon. Common examples include: - Five-membered rings: Pyrazole, imidazole, thiazole, pyrrole. - Six-membered rings: Pyridine, piperidine, piperazine, pyrimidine, purine. - Fused ring systems: Quinolone, benzimidazole, indole structures (present in approximately $59\%$ of heterocyclic-containing drugs). - Aliphatic Chains: Flexible carbon chains that can rotate. They serve several functions: - Modulating system solubility. - Increasing molecular volume. - Allowing conformational adaptability for optimization of the binding pocket.

Physicochemical Properties and Ionization

Acidity and Basicity - Most drugs are either weak acids or weak bases. - Example of a weak acid: Ibuprofen. - Example of a weak base: Lidocaine (also known as Proclidocaine, Lignocaine, or Gylocaine), used as a local anesthetic.
The Role of pH and Ionization - The physiological system has varying pH levels: - Stomach: Low pH, approximately $pH \approx 2$ . - Intestine: Higher pH, approximately $6.5$ to $7$ . - The behavior of a drug like Ibuprofen changes based on the environment due to ionization: - Weakly acidic drugs are less soluble in acidic environments (low pH) because they do not ionize to a great extent. - Weakly acidic drugs are more soluble in basic/alkaline environments (high pH) because they ionize greatly. - pH definition: The negative log of hydrogen ion concentration ( $-\log[H^+]$ ).

Stereochemistry

Definition - Stereochemistry is the branch of chemistry dealing with the spatial arrangement of atoms within a molecule. - It focuses on how these arrangements affect physical and chemical properties, specifically through chirality and stereoisomerism.
Key Terminology - Stereoisomers: Molecules with the same molecular formula but different spatial arrangements. - Chirality: A property where a molecule has a mirror image that is not superimposable (much like a right and left hand). - Chiral Center: A carbon atom bonded to four different kinds of atoms or substituents. For instance, methane is not chiral because it is bonded to four identical hydrogen atoms. - Enantiomers: Mirror-image molecules that are non-superimposable. They share identical atomic formulas but rotate plane-polarized light in opposite directions. - Diastereomers: Stereoisomers that are not mirror images and are not superimposable (e.g., cis-trans, Z and E isomers). They occur when molecules have two or more chiral centers.
The R/S System - A system used to describe the configuration of a chiral center. - Substituents are assigned numbers (priorities) based on higher molecular weight. - R configuration: When the sequence of priorities is in a clockwise direction. - S configuration: When the sequence of priorities is in an anticlockwise direction.
Optical Activity - Optically active molecules change the angle of plane-polarized light when it passes through a solution of the drug. - This is measured using a Polarimeter, which consists of a light source, a polarizer, and a sample tube. - Molecules are classified based on the direction they rotate light (e.g., D-glucose stands for Dextrorotatory).

Pharmaceutical Significance of Stereochemistry

Efficacy and Activity - Stereochemistry dictates pharmaceutical activity, selectivity, and safety. - In Ibuprofen: - The $S$ isomer is pharmacologically active (anti-inflammatory). - The $R$ isomer is inactive. - Because receptors are three-dimensional structures, they act as a "lock" that only specific "keys" (specific configurations) can fit into.
The Thalidomide Tragedy - In the 1960s, Thalidomide was prescribed to pregnant women for morning sickness. - The drug was a mixture; while the intended isomer ( $R$ ) worked, the ( $S$ ) isomer was present and caused neurotoxic events and severe limb deformations in babies. - Today, Thalidomide is no longer used for that indication but is used in cancer treatments.

Overview of Pharmacology: PK and PD

Pharmacokinetics (PK) - Defined as "what the body does to the drug." - Includes the ADME process: - A: Absorption (e.g., through the gut wall into the blood). - D: Distribution. - M: Metabolism (e.g., in the liver). - E: Excretion.
Pharmacodynamics (PD) - Defined as "what the drug does to the body." - Focuses on the drug binding to a receptor and initiating a cascade of biochemical reactions to produce a therapeutic effect (e.g., paracetamol binding to cyclooxygenase enzymes).

Questions & Discussion

Question regarding Chiral Centers - Student/Audience: Inquiry or observation regarding the number of chiral centers in a provided molecular diagram. - Response: The speaker identified several centers and explained why certain carbons are NOT chiral centers. For example, if a carbon atom is bonded to two hydrogen atoms, it does not have four different substituents and therefore cannot be a chiral center.