Drug Discovery 3

Question 0

what are the 2 parallel strands within compound preparation and target selection/validation ?

Answer 0

chemical= choosing/preparing the compounds and libraries for screening
biological= identifying/validating the target, developing the screening assay
- this is divided into target identification, target validation and assay development/hit validation

Question 1

what are the 3 parts of the discovery phases in modern drug discovery and development ?

Answer 1

1- compound preparation and target selection/validation- this ends with a high throughput screen with the output being validated “hits”
2- lead finding - compounds in family which are related
3- lead optimisation- result is a candidate drug which moves into the development stages

Question 2

what is the target ?

Answer 2

it is the molecular recognition site to which the drug will bind- usually a protein but not always

Question 3

what is normally the first approach to determining the target ?

Answer 3

studying the pathophysiology of the disease that you want to cure
- once you have gained this knowledge it may show some drug target sites

no point targetting a human protein that is very abundant throughout the body

Question 4

what does it mean by using the output of genomic analysis to identify targets ?

Answer 4

the use of knockout and transgenic animals to highlight the importance of certain proteins within a disease

Question 5

what does reverse transcriptase do ?

Answer 5

it converts RNA to DNA

Question 6

what does viral protease do ?

Answer 6

it chops up viral proteins into mature smaller proteins

Question 7

what are to target sites for drugs in the treatment of HIV ?

Answer 7

• inhibiting reverse transcriptase
• inhibiting HIV protease
  this interrupts the life cycle of the virus
  these are good examples where understanding biology has lead to new concepts for drug discovery

Question 8

what are the 4 different ways to finding a suitable target ?

Answer 8

1- analysing the pathophysiological pathway of the disease
2- some proteins are more amenable - attempt to determine their mechanism of action- dont pick a very abundant protein because it will cause many adverse side effects
3- analyse the mechanism of action of existing drugs - try and develop a greater understanding of this mechanism may help to develop a more effective drug
4- molecular genomics- knock-outs - observing the effects when a protein is knocked out

Question 9

what is target validation ?

Answer 9

“experimental approaches by which a potential target can be tested and given further credibility “

Question 10

what is the test for target validity ?

Answer 10

the clinical trials- if a drug is taken to clinical trials and has no efficacy then it is disastrous because development is very expensive !

for a drug to go to clinical trials it requires convincing in vivo pharmacological or molecular genomic data

Question 11

what is an assay ?

Answer 11

it is a reproducible experiment

Question 12

what is used to assess compound potency ?

Answer 12

a primary biological screen that is relevant to that disease
a high throughput screen is developed to try and closely match the biological mechanism required for therapy

Question 13

what are the secondary pharmacological models ?

Answer 13

these are used to prove a link between the compound potency and the potential therapy

• these include in vivo or in vitro models that closely reflect the pathology of the disease your trying to treat
• determining whether the hits from the high throughput screening are showing efficacy in treating the disease

Question 14

what did hacker et al mean by “CREDENTIALISING”?

Answer 14

ensuring that the target in you want the drug to work at has the effect intended

Question 15

what happens to primary hits produced from the primary biological screen ?

Answer 15

they are checked in more thoroughly screening - full concentration repsonse curves
then they are run in a secondary pharmacological assay to ensure there is link between the compound potency and treatment- this produces confirmed/validated hits

Question 16

what are the 3 approaches to discovery “hits”?

Answer 16

library based
ligand based
structure based/target based

Question 17

what can each of the approaches to discovering hits result in ?

Answer 17

all can produce hits that can then undergo a more focussed combinatorial library

Question 18

what is library based discovery of hits ?

Answer 18

screening of a large diverse compound library (100000) via high throughput screening

Question 19

what is ligand bases discovery of hits ?

Answer 19

use of focussed library based on either a natural ligand (endogenous based design) or on an initial hit from high throughput screening or a known drug (analogue based design) to cause further ligand synthesis - these structures could be the starting point for discovering a drug with improved properties

Question 20

what is structure-based/target based?

Answer 20

structure of the drug target is used as a guidline to produce a ligand and cause further ligand synthesis

Question 21

what are in silico based methods?

Answer 21

they can be used in all 3 approaches of disovering hits
computational based approaches to focus the companies compound library, to carry out virtual sreening and to carry out pharmacophore or binding site analysis to direct further ligand synthesis

Question 22

how did library based approach lead to the discovery of tipranavir to treat HIV?

Answer 22

HTS lead to a hit= warfarin
this had some moderate inhibitory activity at HIV-protease
this molecule then underwent many stages to yield tripranavir- during this process the structure of HIV proteinase was used, therefore also an input via structure based elements

Question 23

how did ligand based discovery lead to the production of saquinavir ?

Answer 23

it was known that LNFPI was recognised by HIV protease
so the critical bond that was cleaved by HIV protease was replaced to a hydroxyethylene bioisostere which couldnt be cleaved
then other small changes were made to improve stability, efficacy and affinity and this led to saquinavir

Question 24

what structural based approach was taken to produce a drug against HIV protease ?

Answer 24

it was known that HIV protease was symmetrical so symmetrical compounds were produced
this produced ritanovir- it couldnt be cleaved because the critical peptide bond had been altered

Question 25

how many possible molecules are there for pharmaceutical companies to use ?

Answer 25

10 to the power of 60 - therefore it is impossible to make all possible compounds

Question 26

why do pharmaceutical companies want a diverse collection of compounds ?

Answer 26

it increases their chances of finding a starting point

Question 27

why are natural compounds so important ?

Answer 27

they are good at diversifying chemical space

Question 28

what is an example of the production of a drug from a natural compound ?

Answer 28

taxol- chemotherapy agent which promotes microtubule polymerization for breast cancer
it was originally from the taxus brevifolia and extracted from this was a very complex compound that probably wouldnt have been discovered from synthetic compounds because it is too complex

Question 29

what does it mean by focussed library synthesis ?

Answer 29

it involves making a focussed library to look at using combinatorial approaches
- they look at info produced from previous studies - known ligands, in silico screening, molecular modelling, mutagenesis, HTS this makes the search more specific