Introduction and GPCR's

Introduction and GPCR's

1. Targeting receptors

   • Why target receptors?
     • receptors = Proteins that signal following activation (Drug binding)
     • Easier than trying to penetrate membrane
     • Specific unlike ubiquitous proteins
       • Less off target effects
   • Small molecule drugs
     • Targets
       • Proteins
         • Interested in proteins that naturally bind ligands
           • E.g. Receptors
           • E.g. kinases
             • Have regulatory domains
           • E.g. enzymes
             • Have substrate binding sites
       • Lipids
       • Polysaccharides
       • Nucleic acids
   • GPCR's are a good target

2. Asthma

   • Symptoms
     • shortness of breath, especially breathing out, cough
     • Inflammation of the airways
     • Bronchial hyper-reactivity
     • Reversible airways obstruction
     • Worse in late phase
       • More damaging in long term
       • Lead to permanent damage in lungs
   • Anti-asthmatic drugs
     • Bronchodilators (salbutamol)
       • Polymorphisms in β2- adrenoceptors associated with reduced efficacy of bronchodilators
     • Anti-inflammatory agents (prednisolone & omalizumab)
       • Steroids
         • Have side effects
         • Not good to take long term
         • Prednisolone
       • Omalizumab
         • Biological
         • Monoclonal antibody
           • Targets antibodies responsible for allergy
         • Very expensive so restricted to most severe cases
     • Abuse of inhalers
       • Hard to minimise
       • Receptors become desensitised
         • Would be better if we could minimise this
   • Designing new drugs for asthma
     • What do we need to consider?
       • Understand the disease
       • Identify receptors that may be involved
         • Understand receptors
           • Expression
           • Structure
           • Signalling
           • Function
       • Potential off target effects and toxicity
       • Model system
         • Not people
           • Dangerous
         • Not animals
           • Unethical
           • Expensive
         • Cell line expressing receptor of interest
           • What to measure
             • Binding
               • Fits receptor?
             • Downstream signalling
               • Use an assay that quantifies this signalling

3. GPCR's

   • Families
   • Features
   • FRET analysis of GPCRs

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