Multivariate quantitative structure-toxicity relationships in a series of dopamine mimetics.
The techniques of principal components analysis and non-linear mapping are routinely used by computer chemists at SmithKline Beecham Pharmaceuticals in the process of drug development by relating the structure of a compound to its chemical activity. To our knowledge these techniques had not previously been applied to the association between the structure of a compound and its toxicological properties. Using a series of 12 structurally related compounds (11 were active dopamine mimetics and one was inactive), of which five were known to be teratogenic and seven were non-teratogenic, it was possible to demonstrate that molecular modelling techniques could be applied to differentiate toxicological data. The structure/property relationships of these compounds were investigated using calculated physicochemical properties, molecular modelling and multivariate statistical techniques. A data set of 56 molecular descriptors was used to represent this series of compounds. Analysis of the data set using principal components analysis and non-linear mapping suggested that teratogenicity was associated with four molecular properties. Moreover, the electronic nature of the 4-phenyl group appeared to be an important determinant of the teratogenesis.
SmithKline Beecham Pharmaceuticals, Welwyn, Herts, UK.
J E
JE
Ridings
D T
DT
Manallack
M R
MR
Saunders
J A
JA
Baldwin
D J
DJ
Livingstone
D000014:Abnormalities, Drug-Induced / Q000209:etiology; D055598:Chemical Phenomena; D002627:Chemistry, Physical; D003201:Computers; D015259:Dopamine Agents / Q000633:toxicity*; D008954:Models, Biological; D008956:Models, Chemical; D008958:Models, Molecular; D015999:Multivariate Analysis; D013329:Structure-Activity Relationship
D015259:Dopamine Agents