3D-QSAR analysis and molecular modeling investigations of piritrexim and analogous

Quantitative structure-activity, relationships for piritrexim and analogues acting as inhibitors of tumour cell growth have been derived. First the Free-Wilson-method was used on a homologous training set of night derivatives. The selection of variables important for the biological activity of the compounds was carried out with different multivariate methods as multiple linear regression, the partial least squares method and a genetic algorithm. The derivation of three-dimensional structure 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 charges were calculated with the AM1 hamiltonian. For the superimposition of the derivatives two methods were used: maximal similarity of the common substructure or of the molecular fields. A Comparative Molecular Field Analysis with steric and electrostastic fields identified regions important for the activity of the studied compounds independent of the chosen alignment and also correctly predicted the activity of two nonhomologous compounds.