Drugs Discovered using Modelling

To reiterate, GRID does not prediet ehanges in free energy, rather enthalpy, but the predietions led to a strong hypothesis—that ehanging the hydroxyl to an amine would improve aetivity— whieh was eonlirmed by experiment as a 

The hormone angiotensin causes a rise in blood pressure through its action at the angiotensin receptors. The first compounds that were discovered to control hypertension by blocking this pathway were peptide analogues of angiotensin, for example the octapeptide, saralasin. As might be expected, these had poor 

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Schmitt, W Willmann, S. Erratum (Physiology-based pharmacokinetic modeling ready to be used. Drug Discov Today Tech, DO I 10.1016/j.ddtec.2004.09.006). Drug Discov Today Tech 2005, 2 125-132. 

Contrera JF, MacLaughlin P, Hall LH, Kier LB. QSAR modeling of carcinogenic risk using discriminant analysis and topological molecular descriptors. Curr Drug Discov Technol 2005 2 55-67. 

Vandenhaute E, Sevin E, Hallier-Vanuxeem D, Dehouck MP, Cecchelli R (2011) Case study adapting in vitro blood-brain barrier models for use in early-stage drug discovery. Drug Discov Today 17(7-8) 285-290... 

Ginai M, Elsby R, Hewitt CJ et al (2013) The use of bioreactors as in vitro models in pharmaceutical research. Drug Discov Today 18(19-20) 9 22-935, pii S1359-6446(13)00162-l... 

Xie, W. and Evans, R. M. (2002) Pharmaceutical use of mouse models humanized for the xenobiotic receptor. Drug Discov. Today 7, 509-515. 

A second objective is to produce behavioural changes in animals that are analogous to depression so that the model can be used to discover its neurobiological cause(s). This is a far more demanding problem and its success rests on satisfying at least three criteria (see Willner 1984) face validity (i.e. the behaviour looks like depression), construct validity (i.e. the causes and consequences of the behavioural change are the same as in depression) and predictive validity (i.e. the behaviour is reliably prevented only by drugs which have antidepressant effects in humans). 

Predictive validity is the ability of a model to predict the effect that pharmacological or other manipulations will have on the condition being modeled. This criterion can present a real difficulty, in that drug development is often dictated by animal models. For example, if a given model only detects a subset of effective compounds (i.e. those belonging to a specific chemical class), then useful candidates will be discarded long before clinical trials, and the flaw in the model s predictive validity will not be discovered. Thus, the possibility that a model will yield false negatives cannot be ruled out. 

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