Drug Discovery Flashcards
What are some physicochemical properties for an orally active drug?
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
What else must be considered in physicochemical properties?
number of aromatic groups
number of rotatable bonds
polar surface area
presence of known toxic groups
What are tools for modern drug discovery?
recombinant proteins
large compound libraries
high throughput screening
What is screened in drug discovery?
repurpose drugs
tool molecules
demonstrate ligandability
What are the sources of chemical starting points?
existing drugs endogenous ligands natural products fragment screening focussed screening diversity screening rational design
How many compounds does diversity screening cover?
100000-1000000 compound
What is good for HTS?
does not need any knowledge of natural ligands or mode of binding
What is the issue of HTS?
large amount of data to analyse
integrity of compound collection
How many compounds does focused screening look at?
1000-10000
What does focussed screening look at?
well characterised proteins and target families
structure based drug discovery
What are the applications of rationale drug design?
useful in conjunction with fragment and focussed screening
useful in refining activity of existing ligand series
crystallography may provide info about mechanism of action
What does fragment screening do?
follows rule of 3
MW less than 300
logP less than 3
less hydrogen bond donors than 3
How do you optimise fragment screening?
optimise by adding to the molecule
limitations of fragment screening
What are the pros of fragment screening?
smaller libraries
potential to produce better fitting compounds
better starting points
What are the cons of fragments screening?
fragments have low potency
specific/specialised assay tec
need crystal structure
How might you screen for GPCRs?
radioligand binding assays GTPyS Functional cell based assay Calcium sensitive dye screening Alphascreen
What is the b-arrestin Assay?
complementation assay - agonist elicited recruitment of b-arrestin
How is the pharmacokinetics of lead compounds optimised?
look at the the route to absorption
how well it dissolves, pH, intestinal bacteria
liver metabolism
active transport to bile etc
What is the aim of DMPK?
to promote the rapid selection and progression of compounds with human DMPK properties appropriate to the intended therapy and dosing regimen
What does in vitro metabolism assays look at?
liver microsomes
liver hepatocytes
What pharmacokinetic parameters must be met?
t1/2 Cmax bioavailabilty clearance 1st pass metabolism
What factos are important for absorption?
diffusion active transport passive paracellular transport absorption by p-gp receptor mediated transport
What is the CCR5 receptor a target for?
HIV infection
Where is CCR5 expressed?
on immune t-cells and macrophages
What does reduced CCR5 expression do?
cause HIV resistance
What was found to be a anti-viral against CCR5?
Maraviroc
What is maraviroc?
highly selective CCR5 antagonist
Where does maravoric bind?
to a deep pocket in residues of TM I, II, III,IV, V, VI and VII
allosteric site blocks agonist
What is important in drug safery?
regulatory guideline cellular toxicity assess behaviour of animals analysis of blood samples histopathology
What are important considerations in cardiovascular safety?
BP
HR
cardiac arrythmias
What is torsades de pointe?
drug induced arrhythmia
What needs to be considered for cardiovascular safety?
blockade of hERG channel
What are some cardiac safety channels?
hERG
hNav1.5
L-type Ca
What other forms of toxicity are important?
reproductive toxicity
teratogenicity
cancers
How are the toxicities tested?
in vivo in animals
What are the limitations to in vivo tests?
expensive
developmental differences
species difference
What are the limitations of in vitro tests?
false pos and negs
metabolism into teratogen
What was withdrawn after drug launch?
COX 2 Inhibitors
Why were COX 2 inhibitors removed?
increases risk of heart attack and stroke
What was a problem in TRPV1 antagonists?
caused life threatening increases in body temp
What are some translational biomarkers?
Efficacy
Pharmacokinetic
Safety
Predictive
What can translational biomarkers affect?
the Phase 0 study
go or no go decisions
non-invasive assessment
What are important considerations?
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
What happens in personalised medicine?
treatment outcomes depend on genotype such as in breast cancer
What are some mutations in breast cancer?
ER positive
HER2 positive - over expression of EGF
BRCA1 and BRCA2 - DNA damage repair issues
