preclinical drug discovery methods
screening by target
phenotype screening
natural substance modification
biologics
259 agents approved by FDA between '99-08
75 w/new molecular mechanisms of action
50 small molecules
25 biologics
28 were developed using phenotype screening
17 were developed using target based
drug discovery main focus since 1990's has been on targets - clone the receptor or protein and modify it, the rational basis
tools that aid the discovery of compounds - high throughput, x-ray crystallography, computational modelling/screening
prior to molecular era of the 90's was phenotypic screening - less emphasis on mechanism of action
pros/cons of target vs phenotypic screening
target based discovery
pro
hypothesis driven based on molecular/chemical knowledge, all biologics are discovered this way
con
the hypothesis is not useful because it is not involved in pathophysiology
phenotype screening
pro
do not need to know mechanism of action
cons
without mechanism, designing is difficult because don't know which properties to modify, also - screening can be less efficient (low throughput)
the following is a list of CNS drugs approved for these years (taken from their table), most do not have an identifiable target, and 3/7 do not have a known MMOA
Target MMOA
Levetiracetam unknown unknown
Memantine receptor receptor kinetics
rufinamide unknown unknown
varenicline ion channel partial agonist
zonisamide unknown unknown
ramelteon receptor equilibrium binding
discoveries by modification of natural substance
acamprosate ion channel modulator
term
biochemical efficiency - binding affinity/functional response (Ki/EC50)
28 of the first in class small molecules were identified with phenotypic screening -
25 were intentionally targeted, 3 incidentally discovered
MOA were reversed engineered after observing physiological phenomena
18/50 first in class molecules came from natural substances
ramelteon - a melatonin receptor agonist approved for insomnia was discovered with a target specific strategy.
biologics - large peptide molecules - all created using target based approach
enzyme replacement
novel functioning
inhibition of normal function
augmentation of normal function
phenotypic approach worked best for CNS and ID, target based approach worked well for cancer, ID, and metabolic disease
