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Quantative Pharmacology > Drug Discovery > Flashcards

Drug Discovery Flashcards

1
Q

What are some physicochemical properties for an orally active drug?

A

MW less than 500
Lipophillicity is less than 5
no. of hydrogen bond donors is less than 5
no of bond acceptors is less than 10

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2
Q

What else must be considered in physicochemical properties?

A

number of aromatic groups
number of rotatable bonds
polar surface area
presence of known toxic groups

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3
Q

What are tools for modern drug discovery?

A

recombinant proteins
large compound libraries
high throughput screening

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4
Q

What is screened in drug discovery?

A

repurpose drugs
tool molecules
demonstrate ligandability

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5
Q

What are the sources of chemical starting points?

A 
existing drugs
endogenous ligands
natural products
fragment screening
focussed screening
diversity screening
rational design
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6
Q

How many compounds does diversity screening cover?

A

100000-1000000 compound

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7
Q

What is good for HTS?

A

does not need any knowledge of natural ligands or mode of binding

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8
Q

What is the issue of HTS?

A

large amount of data to analyse

integrity of compound collection

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9
Q

How many compounds does focused screening look at?

A

1000-10000

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10
Q

What does focussed screening look at?

A

well characterised proteins and target families

structure based drug discovery

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11
Q

What are the applications of rationale drug design?

A

useful in conjunction with fragment and focussed screening
useful in refining activity of existing ligand series
crystallography may provide info about mechanism of action

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12
Q

What does fragment screening do?

A

follows rule of 3
MW less than 300
logP less than 3
less hydrogen bond donors than 3

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13
Q

How do you optimise fragment screening?

A

optimise by adding to the molecule

limitations of fragment screening

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14
Q

What are the pros of fragment screening?

A

smaller libraries
potential to produce better fitting compounds
better starting points

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15
Q

What are the cons of fragments screening?

A

fragments have low potency
specific/specialised assay tec
need crystal structure

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16
Q

How might you screen for GPCRs?

A 
radioligand binding assays
GTPyS
Functional cell based assay
Calcium sensitive dye screening
Alphascreen
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17
Q

What is the b-arrestin Assay?

A

complementation assay - agonist elicited recruitment of b-arrestin

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18
Q

How is the pharmacokinetics of lead compounds optimised?

A

look at the the route to absorption
how well it dissolves, pH, intestinal bacteria
liver metabolism
active transport to bile etc

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19
Q

What is the aim of DMPK?

A

to promote the rapid selection and progression of compounds with human DMPK properties appropriate to the intended therapy and dosing regimen

20
Q

What does in vitro metabolism assays look at?

A

liver microsomes

liver hepatocytes

21
Q

What pharmacokinetic parameters must be met?

A 
t1/2
Cmax
bioavailabilty
clearance
1st pass metabolism
22
Q

What factos are important for absorption?

A 
diffusion
active transport
passive paracellular transport
absorption by p-gp
receptor mediated transport
23
Q

What is the CCR5 receptor a target for?

A

HIV infection

24
Q

Where is CCR5 expressed?

A

on immune t-cells and macrophages

25
Q

What does reduced CCR5 expression do?

A

cause HIV resistance

26
Q

What was found to be a anti-viral against CCR5?

A

Maraviroc

27
Q

What is maraviroc?

A

highly selective CCR5 antagonist

28
Q

Where does maravoric bind?

A

to a deep pocket in residues of TM I, II, III,IV, V, VI and VII
allosteric site blocks agonist

29
Q

What is important in drug safery?

A 
regulatory guideline
cellular toxicity
assess behaviour of animals
analysis of blood samples
histopathology
30
Q

What are important considerations in cardiovascular safety?

A

BP
HR
cardiac arrythmias

31
Q

What is torsades de pointe?

A

drug induced arrhythmia

32
Q

What needs to be considered for cardiovascular safety?

A

blockade of hERG channel

33
Q

What are some cardiac safety channels?

A

hERG
hNav1.5
L-type Ca

34
Q

What other forms of toxicity are important?

A

reproductive toxicity
teratogenicity
cancers

35
Q

How are the toxicities tested?

A

in vivo in animals

36
Q

What are the limitations to in vivo tests?

A

expensive
developmental differences
species difference

37
Q

What are the limitations of in vitro tests?

A

false pos and negs

metabolism into teratogen

38
Q

What was withdrawn after drug launch?

A

COX 2 Inhibitors

39
Q

Why were COX 2 inhibitors removed?

A

increases risk of heart attack and stroke

40
Q

What was a problem in TRPV1 antagonists?

A

caused life threatening increases in body temp

41
Q

What are some translational biomarkers?

A

Efficacy
Pharmacokinetic
Safety
Predictive

42
Q

What can translational biomarkers affect?

A

the Phase 0 study
go or no go decisions
non-invasive assessment

43
Q

What are important considerations?

A

does compound reach target
does compound interact with target
does it exert the intended effect
does it exert a beneficial effect on the disease - fMRI, MRI, animal

44
Q

What happens in personalised medicine?

A

treatment outcomes depend on genotype such as in breast cancer

45
Q

What are some mutations in breast cancer?

A

ER positive
HER2 positive - over expression of EGF
BRCA1 and BRCA2 - DNA damage repair issues

Quantative Pharmacology (9 decks)

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