hit/ lead compounds

Question 1

what are the steps of the drug development process?

Answer 1

basic research
early dicovery
preclinical
clinical development
review
post marketing monitoring

Question 2

what steps are involved in vitro and in vivo testing?

Answer 2

basic research
early discovery
pre clinical

Question 3

what steps are in volved in human testing?

Answer 3

clinical development
(phase 1,2,3)

Question 4

what steps are involved in data review and surveillance?

Answer 4

review
post marketing monitoring

Question 5

what is target validation?

Answer 5

disease association, cell-based models, protein interactions

Question 6

what are the factors for chosing a disease?

Answer 6

need for a new drug
economical factor

Question 7

what are the factors for chosing a drug target?

Answer 7

biomacromolecules
target specificity/selectivity between species
target specificity/ selectivity within the body
targeting specific organs/ tissues
multi-target drugs: combination therapy and multi-target direct ligand
target validation

Question 8

how to identify a bioassay in vitro testing?

Answer 8

specifoc tissues, cells, enzymes
use bacteria and yeast to produce enzymes
isolated tissues or cells expressing a receptor
intracellular and extracellular events
PK properties

Question 9

how to identify a bioassay in vivo testing?

Answer 9

induce a clinical condition in the animal
transgenic animals
slow and expensive
sometimes results are invalid
variability according to the species

Question 10

what is High-throughput screening (HTS)?

Answer 10

automated tet of large number of compounds against a large number of targets: efficient to hit identification

Question 11

what are the steps of NMR screening?

Answer 11

1) NMR spectrum of the drug is taken
2) protein is added and the spectrum is re-run
3) drug is not binding; its NMR spectrum will still be detected
4) drug binding; no NMR spectrum will be detected

Question 12

what is Isothermal titration calorimetry (ITC)?

Answer 12

determine the thermodynamic properties of binding between a drug and its protein target- the binding affinity and enthalpy change

Question 13

what are the steps of finding a hit compound?

Answer 13

1. screening of natural products
2. screening synthetic compound libraries
3. existing drugs
4. starting from the natural ligand or modulator
5. serendipity
6. computer-aided design (CADD)
7. fragment- based hit discovery

Question 14

what is a pharmacophore?

Answer 14

binding group types essential for activity and their 3-D arrangemnt in the active molecule

Question 15

what is a lead compound?

Answer 15

compund highly active on the target, effective in the disease model, amenable to synthetic modifications, drug-like properties

Question 16

what are drug-like properties?

Answer 16

water solubility
logP
molecular weight
presence of PAINs
Presence of Toxicophoric groups

Question 17

what is lipinski’s rule of five?

Answer 17

relative molecule mass (>500)
number of H-bond donating groups (<5)
number of H-bond accepting groups (<10)
log P (<5)

Question 18

what are isosters?

Answer 18

atoms or groups of atoms which share the same valency, size and which have chemical or physocal similarities

Question 19

what are bioisosters?

Answer 19

retain similar biological properties; useful in lead modification to improve Admey properties

Question 20

what makes a good drug?

Answer 20

effective in targeting a disease process
not toxic
absorbed well by the body
able to easily reach its target
not modified/ removed too quikly from the body

Question 21

how can we optimise access to the target?

Answer 21

1. oprimise hydrophilic/phobic properties
2. making drugs more resistant to chemical and enzymatic degradation
3. targeting drugs
4. Prodrugs

Question 22

what are prodrugs?

Answer 22

compounds which are inactive in themselves, but which are converted in the body to the active drug by enzymes