L21 - genomics and pharmacology (receptors)

Question 1

list some examples of drug targets and what they have in common

Answer 1

enzymes
transporters 
receptors 
ion channels
pumps 
all protein

Question 2

what are some non protein drug targets

Answer 2

DNA & MRNA

Question 3

how is a receptor gene cloned

Answer 3

1. extract mRNA
2. convert to cDNA
3. amplify using PCR
4. separate into cells
5. screen with the ligand for the receptor
6. once found, sequence

Question 4

why clone a receptor gene?

Answer 4

1. gives sequence of drug target
2. allows transfer to other organisms
3. allows modification
4. gives AA sequence
5. tells us which chromosome the gene is on
6. can identify any links to disease

Question 5

what does AA sequence of a drug target tell us

Answer 5

1. info on structure
2. info on function
3. identify similar proteins
4. identify mutations
5. identify important parts eg domains

Question 6

list 4 classifications of receptor

Answer 6

1. GPCR (class A,B,C)
2. ion channel receptors (cys loop, glutamate
   receptors, purinoceptors)
3. intrinsic enzyme receptors (insulin)
4. DNA binding Receptors (testosterone receptor)

Question 7

explain the concept of rational drug design

Answer 7

when we have genomic knowledge of drug targets it allows identification of possible binding sites and any conformational shape changes which helps design a drug that will ‘fit’

Question 8

explain the concept of reverse pharmacology

Answer 8

1. start with common receptor sequence
2. search genome database - identify it as unknown receptor (orphan)
3. then experimentally find the ligand that it binds

usually work in reverse, starting with the ligand and finding a receptor that will bind)

Question 9

explain the adverse drug effects due to drug&gene interaction (halothane)

Answer 9

1. halothane used to be a general anaesthetic, some patients experienced adverse effects such as
   increased skeletal muscle metabolism
   increased muscle contraction
   which caused hyperkalemia
   which caused acidosis
   rapid increase in body temp (malignant
   hyperthermia)

Question 10

what was the cause of the adverse effects of halothane

Answer 10

patients had a mutation in the Sarcoplasmic Reticulum Ca2+ release channel (ryanodine receptor) which meant it could be activated by halothane
which lead to Ca2+ being released into skeletal muscle

Question 11

explain concept of personalise medicine

Answer 11

individuals gene sequence can allow production of medicine that will specifically help an individual based on their DNA
increased effectiveness
decreased adverse effects

Question 12

explain concept of gene therapy

Answer 12

replacing a dysfunctional/mutated gene with a functional one

Question 13

limitations to gene therapy

Answer 13

1. difficulty getting gene into a cell (across membrane)
2. difficulty then getting gene into target/specific cell
3. need to stop the mutant gene from functioning
4. have to control expression of the new gene
   5 have to be careful that the new gene doesnt interact with existing ones