drug discovery review

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