IC11

• Macro


  • Altering microorganism biosynthesis or microbial proteins
  • Interaction with other molecules (e.g. water, toxins)
  • Acting on targets in human body
• Macro drug targets


  • Microorganism
  • Physical
  • Chemical
  • Human body
• Microorganism drug targets


  Antibiotics, antivirals
• Chemical drug targets


  e.g. antacids
• Cellular drug targets


  • On cell surface
  • Within cell
• Protein drug targets within cell

  • Transport systems
  • Ion channels
  • Carrier molecules
• Ion channels


  • Proteins that form pores in cell membrane to allow selective transfer of ions
  • Opening/closing of channel ("gating") can be controlled by Neurotransmitter (ligand-gated) or Membrane potential (voltage-gated)
  • Drugs can block or modulate these channels
• Carrier molecules


  • Energy-independent or energy-dependent carriers; drugs can Inhibit the transporters or Be a "substrate" for the transporter
• Micro (protein) drug targets

  • Enzymes
  • Receptors
• Enzymes


  • Protein catalysts that increase rate of specific chemical reactions
  • All enzymes are potential targets for drugs
  • Drugs can Inhibit enzymes, Act as a false substrate (competition), or Use the enzyme to convert itself from a prodrug to an active drug
• Receptors


  • Endogenous ligands produce their effects on cells via receptors
  • Types of ligands: Agonists, Antagonists, Examples: Neurotransmitters, Hormones
  • Drugs can Modulate receptor number or Modulate responsiveness of receptor to external ligand
• Non-protein drug targets


  • Nucleic acids
  • Lipids
• Pharmacological receptors


  • Intracellular or membrane-bound proteins which produce a pharmacological effect after binding with a specific ligand
  • The component of a cell or organism that interacts with a drug and initiates the chain of events leading to the drug's observed effect
• Types of pharmacological receptors

  • Membrane-bound receptors
  • Intracellular receptors
• Membrane-bound receptors


  • Ligand-gated ion channels (ionotropic receptors)
  • G protein coupled receptors (GPCR, metabotropic receptors)
  • Kinase-linked receptors
• G protein coupled receptors (GPCR)


  • Single polypeptide chain with 7 transmembrane-spanning α helices, binding domains embedded within the membrane
  • G-protein: A trimmer consisting of α,β and γ sub units, not attached to receptor in resting state, binding of agonist to receptor causes a series of steps to activate G-proteins, activated G-proteins in turn produce other molecules intracellularly and illicit signal amplification
  • Examples: dopamine, serotonin
• Intracellular receptors


  • Nuclear receptors (nucleic acids), causes changes in transcription and translation activity
• Receptor theory/concepts


  • Lock and key model
  • Induced fit model
• Non-covalent drug-receptor interactions


  Reversible and weak interactions, decreasing over distance, Types: Ionic, Hydrogen bonding, Van der Waals forces, Hydrophobic interactions
• Covalent drug-receptor interactions


  Strong irreversible bonds, high bond energy
• Factors affecting drug-receptor interactions

  • Chemical structure of drugs: Functional groups, Physicochemical properties (size, shape, lipophilicity), Spatial arrangement (stereoisomers)
  • Structure-activity relationship (SAR)
• Drug binding affinity


  Affinity ∝ (1/K_d )
• Constitutive receptor activity


  • Some appreciable baseline activity even without agonist binding
• Two-state receptor model


  • Two states: active and inactive states, confers different drug affinity for receptor
• Agonists


  • Full agonists: Has affinity for the active receptor, but no affinity for the inactive receptor, drives equilibrium to the active state, increasing response
  • Partial agonists: Moderately greater affinity for the active receptor than for the inactive receptor, driving equilibrium to the active state but to a smaller extent, producing smaller response than a full agonist
  • Inverse agonists: Affinity for the inactive receptor but no affinity for the active receptor, drives equilibrium to the inactive state, decreasing basal response for receptors with constitutive activity
• Antagonists


  • Same affinity for the active and inactive receptor, does not alter the equilibrium between active receptor and inactive receptor, basal response not affected
  • Competitive antagonists: Competes and occupies the same receptor binding site(s) as the agonist, interaction b/w antagonist and the binding site is freely reversible
  • Allosteric/Noncompetitive antagonists: Binds to a site other than the binding site on the receptor, upon binding, 3D structure of the receptor is altered, commonly irreversible or near irreversible interaction, effect cannot be overcome by increasing agonist concentration
• Ligand-gated ion channels

  1. membrane bound receptor
  2. ionotropic receptors
  3. fast
  4. usually involved in fast synaptic neurotransmission
• G protein-coupled receptors

  1. membrane bound receptor
  2. metabotropic
  3. relatively fast
  4. trigger release of hormones, neurotransmitters, smooth muscle contraction, ion transport etc
• kinase-linked receptor

  1. membrane bound receptors
  2. slow (mins-hours)
  3. usually involved in regulation of growth, differentiation
• nuclear receptor

  1. intracellular receptor
  2. slow
  3. effects usually last longer, usually involved in growth, metabolism
• this formula is the equilibrium dissociation constant, reciprocal of which describes drug binding affinity