Drug Discovery Flashcards
(45 cards)
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
