A novel electron-conformational approach to molecular modeling for QSAR byidentification of pharmacophore and anti-pharmacophore shielding

A novel method of pharmacophore identification and activity prediction in s tructure-activity (structure-property) relationships is worked out as an es sential extension and improvement of previous publications. In this method each conformation of the molecular systems in the training set of the SAR p roblem is presented by both electronic structure and geometry parameters ar ranged in a matrix form. Multiple comparisons of these matrices for the act ive and inactive compounds allows one to separate a smaller number of matri x elements that are common for all the active compounds and are not present in the same arrangement in the inactive ones. This submatrix of activity r epresents the pharmacophore (Pha). By introducing the Anti-Pharmacophore Shielding (APS) defined as molecular groups and competing charges outside the Pha that hinder the proper docking of the Pha with the bioreceptor, the procedure of Pha identification is es sentially reduced to the treatment of a smaller number of simplest in struc ture most active and inactive compounds. A simple empirical scheme is sugge sted to estimate the APS numerically, while the contributions of different conformations of the same compound are taken into account by means of Boltz mann distribution. This enables us to make approximate quantitative predict ions of activities. In application to rice blast activity we reached an approximately 100% (wit hin experimental error) prediction probability of the activity qualitativel y (yes, no), and with r(2) = 70% quantitatively.