R. Fleischer et al., 3D-QSAR ANALYSIS AND MOLECULAR MODELING INVESTIGATIONS OF PIRITREXIM AND ANALOGOUS, JOURNAL OF MOLECULAR MODELING, 3(8), 1997, pp. 338-346
Quantitative structure-activity, relationships for piritrexim and anal
ogues acting as inhibitors of tumour cell growth have been derived. Fi
rst the Free-Wilson-method was used on a homologous training set of ni
ght derivatives. The selection of variables important for the biologic
al activity of the compounds was carried out with different multivaria
te methods as multiple linear regression, the partial least squares me
thod and a genetic algorithm. The derivation of three-dimensional stru
cture activity relationships started with a systematic conformational
analysis of all compounds. For the conformations having minimal energy
and being in agreement with the crystal structure of piritrexim charg
es were calculated with the AM1 hamiltonian. For the superimposition o
f the derivatives two methods were used: maximal similarity of the com
mon substructure or of the molecular fields. A Comparative Molecular F
ield Analysis with steric and electrostastic fields identified regions
important for the activity of the studied compounds independent of th
e chosen alignment and also correctly predicted the activity of two no
nhomologous compounds.