Newman

• Pharmacodynamics


  Drug action and mechanism. Drug interactions that result from no change in either drug's concentration.
• Safety and efficacy


  Two main reasons drugs fail in clinical testing.
• Pharmacology


  The study of drug action on biological systems
• Medicinal Chemistry


  The design and optimization of drug molecules.
• Pharmaceutics


  The science of drug delivery systems
• Pharmacokinetics (Absorption, Distribution, metabolism, excretion)


  What the body does to the drug, ADME
• Examples of pharmacodynamics (how the drug effects the body)


  Binding of the drug to its target

  How the drug affects the target function

  The resulting physiological response
• Drugs can only modify existing functions of cells


  Except for gene therapy
• Noncovalent forces are dominant in drug - target binding due to the need for the drug to leave once its job is done
• Drug target activation can lead to many complex responses
• Desensitization


  Decreased ability of a receptor to respond to stimulation by a drug or ligand
• Homologous desensitization


  Decreased response at a single type of receptor
• Heterologous desensitization


  Decreased response at two or more types of receptor
• Inactivation


  Loss of ability of a receptor to respond to stimulation by a drug or ligand
• Down-regulation


  Repeated or persistent drug-receptor interaction results in removal of the receptor from sites where subsequent drug-receptor interactions can take place
• Drugs can bind to more than one target and/or cause more than one effect which could be therapeutic or adverse
• Good drug targets are:

  • Unique
  • Have a proven role in the disease pathophysiology
  • Druggable (accessible to drug molecule)
  • Assayable
  • Its activity can be modulated without significantly affecting normal physiology
• G Protein coupled receptors


  Largest family of drug targets (opiates, serotonin, epinephrine, histamine) as well as the 3rd largest gene family in humans
• Protein kinase phosphorylates proteins
• Second messengers activating protein kinase can affect sensitivity of receptors or expression of genes in the long term, and can result in amplification - interconnections
• The type of g protein determines...?

  What is activated
• Enzyme-linked receptors:

  1. Ligand binding causes receptor dimerization
  2. Dimerization makes enzyme domains catalytically active which leads to autophosphorylation
  3. Phosphorylation of target proteins leads to a cellular response
• Transporters are a major function in neurotransmitter recycling in the brain which make them a target for some CNS drugs
• In regards to drugs affecting transporters

  Drugs generally block the transport of substrates
• In regards to drugs targeting enzymes

  Drugs generally inhibit enzyme activity
• Kinase inhibitors prevent the domino effect that is caused by protein kinase activation and are a major class of drug
• Monoclonal antibodies are made by injecting a subject with an antigen and retrieving the antibodies made to fight it.


  They are incredibly effective but equally expensive
• In regards to drugs targeting nucleic acids


  Drugs generally modify the acids to inhibit replication, transcription, and/or translocation

  
  

  Think tumors!
• RNAi basically makes an antagonist for the RNA pair so that it stops replicating the unwanted thing
• Drugs can bind cell membrane phospholipids and disrupt membrane permeability
• Omics based novel targets

  Looking at gene/protein changes en masse

  
  

  Big picture: What's the difference in the genome of the sick population
• The genome is an indirect marker for understanding disease. Proteins are what actually execute physiological functions
• Proteomics (protein genomics) is much more complicated than genomics because while an organism's genome is constant, the proteome differs from cell to cell and time to time
• Phenotype-based drug discovery

  1. Assay development
  2. Screening
  3. Hits and leads
  4. Target deconvolution
  5. Target!
• Target-based drug discovery builds on the growing body of scientific literature about what is causing disease at the molecular level
• Target-based drug discovery can be risky because the approach is inherently biased and once the drug is in clinical trials, there may be complications with the way the drug interacts with the complexities of the human body
• In practice, is phenotype or target-based drug discovery used?

  Both
• HIV is a particularly tough virus because it affects the immune cells, compromising the very cells meant to fight it
• Prediscovery (leads to target identification)


  Understanding the disease
• Target identification (leads to target validation)


  Identify biological targets for the disease