An electron-conformational method of identification of pharmacophore and anti-pharmacophore shielding: Application to rice blast activity

In extension and improvement of previous results, a novel method is worked out for pharmacophore identification and activity prediction in structure-a ctivity relationships. In this method, as in our previous works, each molec ular system (conformation) of the training set is described by a matrix wit h both electron structural parameters (atomic charges, bond orders, etc.) a nd interatomic distances as matrix elements. This description includes a ra ther full geometry of charge and/or reactivity distribution thus providing a much better representation of the molecular properties in their interacti on with the target. By multiple comparison of these matrices for the active and inactive compounds of the training set, a relatively small number of m atrix elements are revealed that are common for all the active compounds an d are not present in the same combination in the inactive ones. In this way a set of electronic and geometry parameters is obtained that characterize the pharmacophore (Pha). A major improvement of this scheme is reached by i ntroducing the anti-pharmacophore shielding (APS) and a proper treatment of the conformational problem. The APS is defined as molecular groups and com peting charges outside the basic skeleton (the Pha plus the inert neighbor atoms that do not affect the activity) that hinder the proper docking of th e Pha with the bioreceptor thus diminishing (partially or completely) the a ctivity. A simple empirical formula is derived to estimate the relative con tribution of APS numerically. Two main issues are most affected by the APS: (1) the procedure of Pha identification is essentially simplified because only a small number of molecular systems with the highest activity and simp lest structures (systems without APS) should be tried for this purpose; (2) with the APS known numerically, we can make a quantitative (or semiquantit ative) prediction of relative activities. The contributions of different co nformations (of the same molecular system) that possess the Pha and differe nt APS is taken into account by means of a Boltzmann distribution at given temperatures. Applied to an example, rice blast activity, this approach pro ved to be rather robust and efficient. In validation of the method, the scr eening of 39 new compounds yields approximately 100% (within experimental e rror) prediction probability of the activity qualitatively (yes, no), and w ith r(2) = 0.66 quantitatively.