Advanced Medicinal Chemistry Lecture 1

Advanced Medicinal Chemistry Lecture 1: Target Classes

• Drug Discovery Process: A diagram illustrates the stages involved in discovering drugs, ranging from Target Identification to Candidate Drug (CD) development.
• Timeframes: Various stages have different time allotments. Target Identification spans 3 months to 2 years. HTS (High-Throughput Screening) takes 3-4 months. Active-to-Hit (AtH) takes 3 months. Hit-to-Lead (HtL) takes 6-9 months. New Lead Optimisation Projects (LO) take 2 years to develop into a Candidate Drug (CD).

Taxonomy of Biological Mechanisms

• In vivo Effectors: A branching diagram demonstrates how different biological mechanisms, relating to receptors, enzymes, ion channels and protein-protein interactions, can be categorized by their roles in various biological processes within a living organism ("in vivo").
• Receptors: Receptors can be agonists, antagonists, partial agonists or inverse agonists.
• Enzymes: Enzymes can be inhibitors.
• Ion Channels: Ion channels can be openers or blockers.
• Protein-Protein Interactions: Protein-protein interactions can be inhibitors.

Blockbuster Drugs

• Lipitor: An HMG CoA inhibitor, made by Pfizer, costs $12 billion.
• Plavix: An anti-platelet, made by BMS/Sanofi-Aventis, costs $5 billion.
• Nexium: A proton pump inhibitor, made by AstraZeneca, costs $4.8 billion.
• Norvasc: A calcium channel blocker, made by Pfizer, costs $4.8 billion.
• Drugs Mechanism and Types: The diagram shows different types of drugs (such as enzyme or receptor based), and chemical representations of example blockbuster drugs.

Biological Mechanisms (2005)

• Top 50 Drugs by Sales: A pie chart illustrates the distribution of top 50 drugs by mechanism in 2005 categorized by Receptor Antagonist, Enzyme inhibitor, Receptor agonist, Miscellaneous, Biological Modulator, and Ion Channel Modulator.
• Enzyme Function: A diagram shows how enzymes use an active site to bind a transition state during a reaction. It also explains the concept of allosteric binding, which occurs away from the active site.

Enzyme Inhibition

• Four Mechanistic Categories: Four types of enzyme inhibition are listed: competitive, uncompetitive, non-competitive (also called allosteric), and irreversible.
• Inhibitors: In competitive inhibition, inhibitors compete with the substrate for the active site, while in uncompetitive inhibition, inhibitors bind to the enzyme-substrate complex. Non-competitive inhibitors bind at a place other than the active site (allosteric). Irreversible inhibitors bind covalently to the enzyme, inhibiting its function permanently.

Proteases

• Hydrolytic Action: Proteases (proteinases, peptidases) hydrolytically cleave peptidic amide bonds between amino acids in proteins.
• Classes and Characteristics: This includes four classes: serine (ser), cysteine (thiol), aspartic and zinc-based proteases. Different classes have different nucleophiles ("e.g., ser-CH2OH" or "cys-CH2SH") and associated pH preference ranges. Some proteases can act on the inner part of a polypeptide chain (endo) while others only act at the ends (exo).

Protease Specificity

• Side-Chain Binding: Protease specificity is determined by how amino acid side-chains near the cleavage site of a polypeptide bind to the enzyme. The diagram shows the nomenclature used to describe these binding sites (Specificity pockets, or P1 to P3).

Serine Proteases

• Catalytic Triad: A serine protease's catalytic activity depends on a catalytic triad composed of Asp, His, and Ser amino acids.
• Oxyanion Hole: The oxyanion hole is critical for stabilizing the transition state during the reaction.

Receptors

• Membrane-Bound Proteins: Receptors are membrane-bound proteins that bind endogenous ligands, often outside the cell to initiate signal transduction inside the cell.
• G-Protein Coupled Receptors: G-protein coupled receptors (GPCRs) are frequently associated with important physiological cascades.
• Seven Transmembrane Spanning: Seven transmembrane spanning receptors (7TM) structure is detailed.

Binding to Receptors

• Agonist vs. Antagonist: Agonists bind to a receptor, triggering a conformational change resulting in a signal. Antagonists bind, inducing no signal, preventing agonists from binding. Ligands might be small molecules, proteins or peptides.
• Competitive Binding: Agonists and antagonists bind competitively to receptors.
• Binding Characteristics: Endogenous agonists often bind weakly, while successful antagonists often bind tightly.

Ion Channels

• Membrane Potential: Living cells have an essential electrical potential difference across their membranes (60-70 mV).
• Passive Ion Flow: Ion channels regulate passive ion flow across cellular membranes based on electric fields and concentration gradients.
• Structure and Function: Ion channels are proteins with specific ion selectivity.
• Involved Mechanisms: They are key regulators in cardiac, neuronal, and other vital physiological processes.
• Various Types: Ion channels can be categorized as voltage-gated or ligand-gated.
• Ligands: Ligands that act on ion channels can be other ions, small molecules, or toxins.