PCL102 Notes for Final Exam

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School
University of Toronto St. George
Department
Pharmacology
Course
PCL102H1
Professor
Rebecca Laposa
Semester
Winter

Description
Required  Readings     Injecting  Prialt  in  a  fish  will  paralyse  it  because  it  blocks  the  synapses  preventing   clcium  channels  from  opening.     A  drug  must  be   -­‐ potent   -­‐ absorbed   -­‐ Stable   -­‐ Cnvenient   -­‐ Manufacturable   -­‐ Last  safe     Toxicogenomics  –       Pharmacokinetics  –  what  the  body  does  to  the  drug     Pharmacodynamics  –  what  the  drug  does  to  the  body     NDA  –  New  drug  application       Pre-­‐discovery  –  understand  the  disease  and  choose  a  target  molecule   Drug  Discovery  –  Find  a  drug  candidate   Preclinical  Testing    -­‐  Test  extensively  to  determine  if  the  drug  is  safe  for  human   testing     -­‐  NDA  –  obtain  FDA  approval  to  test  in  humans   Clinical  Trials  –  test  in  humans  to  determine  if  the  drug  is  safe  and  effective   Approval  –FDA  reviews  results  of  all  testing  to  determine  if  the  drug  can  be   approved  for  patient  use     Kinase  –  enzymes  that  can  activate  protein  through  the  addition  of  phosphate   groups   Miccroarrays   -­‐ shows  which  genes  are  induced  and  which  genes  are  repressed   -­‐ Generating  microarrays   o mRNA  must  be  isolated  (through  centrifuging)   o Add  buffer  to  pellets   o Remove  from  pellets  and  place  in  fresh  microfuge  tubes   o Reverse  transcriptase  allows  the  synthesis  of  cDNA  from  mRNA   o RNase  degrades  mRNA,  leaving  only  cDNA,  which  are  complementary  to   the  mRNA  and  are  also  the  same  sequence  as  the  antisense  strand   o The  two  different  (in  this  case  aerobic  and  anaerobic)  cultures  are  mixed   together  to  form  a  probe  of  the  microarray   o 6200  probes  for  a  yeast  genome   o cDNA  bind  to  their  complimentary  strand  on  a  particular  on  the   microarray   o use  buffer  to  wash  off  any  unbinded  cDNAs   o then  insert  the  microarray  into  a  scanner  where  the  two  lasers  will   detect  the  two  different  dyes   Retroviruses  reverse  transcribe  their  RNA  into  DNA   HIV    protease  molecule  –  symmetrical  with  a  SINGLE  active  in  the  middle   -­‐ first  drug  made  for  this,  not  water  soluble,  hence,  rendered  useless     Globular  proteins  –  x-­‐ray  crystallography   Spliceosome  –  made  of  150  proteins,  splices  RNA,  stitching  exons  that  get  translated   into  protein  and  relegating  to  introns   It  is  grueling  for  crystallographer  because  of  the  fast  and  continusly  changing   activity   snRNA      (small  nuclear  RNA)  –     HIV  trimer  –     Epidermal  growth  factor  receptor  –     4  ways  to  improve  clinical  trials   -­‐ recruit  early   -­‐ skip  animals   -­‐ use  models   -­‐ alter  course   Public  sector  is  focusing  resources  on  translational  science   -­‐ sustain  drug  discovery  for  short  term   -­‐ no  benefits  to  productivity     Subprojects  for  drug  discovery   -­‐ creation  of  specific,  selective  and  bioavailable  chemical  probesfor  all  human   enzymes   -­‐ generation  of  highly  selective  protein  affinity  reagentsfor  all  human  proteins   -­‐ creation  of  a  wellannotated  dataset  of  toxicity  profiles  for  every  compound  that   has  been  in  cinical  or  pre  clinical  development     Drug discovery is still confounded by our relatively poor understanding of disease mechanisms, particularly in humans. Contra-­‐indicated  –  against  the  indications,  against  what  the  drug  is  approve  for     7  wyas  that  make  clinical  research  ethical:   -­‐ value   -­‐ Scientific  Validity   -­‐ Fair  subject  selection   -­‐ Favorable  risk-­‐benefit  ratio   -­‐ Independat  review   -­‐ Informed  consent   -­‐ Respect  for  potential  and  enrolled  subjects   Plant  medicines  to  global  healt:  we  require  some  paradigm  shifts  –     -­‐ think  of  all  medicines,  whether  natural  or  synthtis,  as  essential,  sustainale   commodities   -­‐ change  the  focus  of  drug  discovery  to  attend  to  the  developing  world’s  disease   needs   -­‐ improve  quality  of  traditional  and  plant-­‐based  medicines   -­‐     Reaction  type  A  –  unwanted   Reaction  type  B  –  unexpected     TCGA  –  The  Cancer  Genome  Atlas   -­‐ catalogue  genomic  changes  in  tumours   -­‐ help  understand  biological  process  of  cancer   -­‐ improve  ability  to  diagnose,  treat  and  prevent     Breast  Cancer   -­‐ Estrogen  receptor  positive   -­‐  -­‐  best  prognosis   o cell  proliferation   o uncrontrolled  growth   -­‐ Human  epidermal  growth  factor  receptor  2   o Expressed  on  the  surface  of  cells   -­‐ First  fully  synthetic  drug   -­‐  -­‐  Salvarsan  for  sleeping  sickness  and  syphilis   -­‐ Serendipity  –  finding  something  you  did  not  seek   -­‐ Analogue: a compound that is structurally derived from another compound   Studying  the  proteome   -­‐ X-­‐ray  crystallography   -­‐  -­‐  finding  shape   -­‐ examines  diffraction  pattern   o grow  protein  crystals   § difficult  because  trillions  of  proteins  must  be  I  a  precise  order   o shine  x-­‐rays   o examine  diffraction  pattern   o infer  structu
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