Advanced Medicinal Chemistry - Lecture 1

Advanced Medicinal Chemistry - Lecture 1: Target Classes

• The lecture is about target classes in advanced medicinal chemistry.
• The drug discovery process has stages: target identification (3-24 months), HTS (3-4 months), Active-to-Hit (AtH) ( 3 months), Hit-to-Lead (HtL) (6-9 months), New Lead Optimisation Projects (LO) (2 years), and Candidate Drug (CD) (2 years).
• Biological mechanisms include receptors (agonists, antagonists, partial agonists, inverse agonists), enzymes (inhibitors), ion channels (openers, blockers), and protein-protein inhibitors.
• Effective drugs, such as Lipitor (HMG CoA inhibitor, $12 billion), Plavix (anti-platelet, $5 billion), Nexium (proton pump inhibitor, $4.8 billion), and Norvasc (calcium channel blocker, $4.8 billion) are part of blockbuster drugs from a list of the top 50 drugs from worldwide sales of 2005.
• Enzyme function involves an active site that binds to the transition state for substrate (S) to product (P).
• Enzyme inhibition can be competitive, uncompetitive, non-competitive (allosteric), or irreversible (suicide).
• Proteases (proteinases, peptidases) hydrolytically cleave peptide amide bonds. They have four mechanistic classes: serine, cysteine, aspartic, and zinc.
• Protease specificity is determined by the binding of substrate amino acid side-chains near the cleavage site. Specific pocket nomenclature is used.
• Serine proteases like thrombin, tryptase, beta-lactamase, elastase, chymotrypsin, and HCV-NS3 have a catalytic triad that boosts serine nucleophilicity.
• Receptors are membrane-bound proteins that bind endogenous ligands (usually extracellular) to induce a physiological effect (usually intracellular).
• G-protein coupled, seven transmembrane spanning receptors are major types of receptors.
• α-adrenoceptors are a type of receptor.
• Binding to Receptors: Agonists bind and induce a signal. Antagonists bind and block signals.
• Ligands can be proteins, peptides, or small molecules.
• Agonists and antagonists bind competitively. Endogenous agonists often bind weakly, while successful antagonists bind tightly.
• Ion channels regulate passive ion flow across membranes dependent on electrical or concentration gradients, and some involve ion channels like hERG (iKr).
• Ion channels can be voltage-gated or ligand-gated. Ligands for ion channels can be other ions, small molecules, or toxins and venoms.