3D-QSAR ANALYSIS AND MOLECULAR MODELING INVESTIGATIONS OF PIRITREXIM AND ANALOGOUS

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.