Drug Discovery 1 Flashcards Preview

E: Quantitative Pharmacology > Drug Discovery 1 > Flashcards

Flashcards in Drug Discovery 1 Deck (51):
1

Definition of a drug?

An active ingredient that is intended to furnish pharmacological activity or other direct effect in the diagnosis, cure, treatment or prevention of a disease.

Or to effect the structure or any function of the human body, but does not include the intermediates used in the synthesis of such ingredients.

2

Lipinskin rule of 5 for the physiochemical properties for an orally active drug?

  • Molecular weight <500
  • lop5 <5 
  • Number of hydrogen bond donors <5
  • Number of hydrgoen bond acceptors <10

3

Additional considerations for the physiochemical properties for an orally active drug?

  • Number of aromatic groups
  • Number of rotatable bonds
  • Polar surface area
  • Presence of known toxic groups

 

4

Physiochemical properties for an orally active drug?

Drugs have basic physiochemical proporties

Keeps the drug safe

5

The drug discovery and development process?

AS47

6

Name the 5 ways to screen for drug discovery?

  • Identify a target implemented in disease.
  • Identification of chemical starting points for drug discovery.
  • Looking for validated hit series which modulates target or cell type of interest.
  • Optimisation of compounds to deliver properties suitable for study in animal models of disease.
  • Develop drugs with the appropriate activity and safety for clinical development

7

Name the 3 tools used for modern drug discovery?

  1. Recombinant proteins (prified or recombinant cell lines)
  2. Large compound libraries
  3. High throughput screening technologies

8

High throughput screening (HTS)

Screen different compounds to see what they do to the receptor.

9

Agonist

 

Binds to the receptor and activates it causes a response

10

Antagonist?

Binds to the same site as agonist

No response

Blocks the site for agonist so they cannot cause a response.

11

Posiive allosteric modulator?

Increase the response

12

Negative allosteric modulators?

Decreases the response.

Binds to another site of the receptor away from the agonist/antagonist

13

HTS approach to HIT identifiactions

A large library of compounds.

Screen each compound for their effect on the drug target.

Might have low affinity or potency etc- need to optimise them

14

Name the 4 things that are screened?

  1. Start points for drug discovery
  2. Repurpose drugs
  3. Produce tool molecules (finding a function for unknown proteins)
  4. Demonstrate ligandability of large.

 

15

What are the sources that are screen for a chemical starting points?

Look at existing drugs

Then expand the search more looking and endogenous ligands and natural products.

Eventually, if a compound is still not found will look at rational design compounds.

Look at a small library first of compounds that should work and eventually will get bigger as the search expands

16

What is the typical number of compounds screened?

100,00 to 1,000,000.

17

What is the chemical space defined as?

All the possible combinations of possible drug molecules

1062

18

What must you have in a library of compounds?

A large and diverse library with a range across the chemical space.

19

How are the compounds of the library stored?

they are stored at a cool temp to stop them from degrading

20

Compound library design

  • Quality of library is essential
  • Representative compounds with potential for optimisation.
  • New compounds set to design to 'lead-like' properties

21

Lead-like properties

6 of them

  1. Molecular weight 180-350
  2. lopP about 1-3
  3. Number rotatable bonds <7
  4. Number of hydrogen bonds donors <3
  5. Number of hydrgoen bond acceptors <8
  6. No structural alert

22

Focused screening?

Keep library small but diverse so you can screen them quickly.

Screening of well characterised proteins (most drugs come from a limited set of protein families)

Structure based drug discovery

23

Linking of target families

Expressed like a phyletic tree.

Particular chemical families- similar sequences

Most drugs come for the same group(s) of  families 

A image thumb
24

Rational Design?

Model of target receptor/enzyme

Either via direct crystal structure or indirect homology model.

25

Name the two rational designs?

  • Compound screening
  • Hit and lead optimisation

 

26

Applications of rationale drug design?

  • Useful in conjunction with fragment and focused screening
  • Useful for refining activity of existing ligand series
  • Crystallography may provide information about mechanism of action

 

27

Why cant we design a drug around the shape of the receptor

Using rational design

It is only a single representation of one confirmation therefore does not account for induced fits

28

Fragment screening?

Fragments have a molecular weight of 100-250

More efficient binding.

Small library but covers a larger chemical space.

 

29

Fragment screening must follow what rule?

What does this rule say?

Rule of 3.

  • MW <300
  • LogP<3
  • Hydrogen donors <3
  • No. Rotatable bonds <3

 

30

What is the negatives of fragment screening?

Could have low potency

Must measure ligand efficiency

31

Ligand efficiency equation?

AS48

32

What does ligand efficiency tell us?

To determine the potency.

Clincically used drugs are usually more potent to decrease the dose needed

33

What are the limiations to fragment screening?

Need crystal structure

Need soluble protein

34

What are the positives and negatives of using fragment screening?

Pros:

Smaller libraries cover larger chemical spaces

potential to produce better fitting compounds

Better starting point

Cons:

Fragments have low potency

Specific technologies

Need crystal structure

35

Two specific technologies used to screen assays?

Automated compound handling

Optical readers for plate based assays

36

Typical screening assays for GPCRs

Radioligand binding assays

Displacement assay- competitive ligands

GTPS assay- agonist/inverse agonist

37

GTPgammaS assay?

agonist can increase the S to GTP binding.

Antagonist decrease agonist stimulated S binding 

Agonist stimulation modulated by PAMs and NAMs

38

Calcium sensitive dyes?

Used in functional cell based assay

AS49

39

Alpha screen assay?

Using florescent light

40

beta-arrestin assay

Agonist elicited recruitment of beta-arrestin.

Catalytic conversion of substrate to a chemiluminescent product

aS50

41

2 ways to screen for biased GPCR ligands?

G protein mediated

Beta-arrestin mediated

42

Equation used by the surface plasmon resonance for fragment screening

KD= K1/K+1

43

The equation used by the isothermal titration calorimetry for fragment screening?

KD=1/KB

44

The two calculations for ligand efficiency?

deltaG=RTInKD

LE=deltaG/N

R: gas constant; t: Absolute temp; N: no. non-hydrogen atoms

45

KD

The dissociation constant.

46

HTS flowchart

AS51

47

Hit optimisation

Synthesis and test a small number of hit analogues

Determine priniciple liabilities for each hit series.

 

48

Lead optimisation?

Focussed SAR campaigne

Transform biologically active compound into clinical drug

49

What must the drug be optimised to prevent?

Prevent dissolve

Survive a range of pH (1.5- 8)

Survive intetsinal flora

Cross membrane

Survive liver metabolism

Avoid active transport to bile

Avoid excretion by kidneys

50

Role of DMPK?

To promote the rapid selection and progression of compounds with human DMPK propoerties

51

Absorption?

Passive, transcellular

Active (linked to ATP) or secondary active (linked to electrochemical gradient)

Facilitated diffusion