I. B. Bersukera,b, S. Bahcecia, J. E. Boggsa and R. S. Pearlmanb

A Novel Electron-Conformational Approach to Molecular Modeling for QSAR by Identification of the Pharmacophore and Anti-Pharmacophore Screening.

a Department of Chemistry and Biochemistry, b College of Pharmacy, The University of Texas at Austin, Austin, TX 78712

The most difficult problem in structure-activity relationships is to model the systems to represent the property sought. In continuation of previous work on this topic, we have developed a method that has three modules:

  1. pharmacophore (Ph) identification using a limited number of most active and similar nonactive compounds of a trial system,
  2. evaluation of the anti-pharmacophore screening (APS) constants using less active compounds of the trial set, and
  3. screening of new compounds with the lectron-conformational (EC) method.

In Ph identification, the electronic and conformational properties of the molecule are combined by means of k EC matrices of congruity (ECMC) of the dimension nxn, where n is the number of atoms in the molecule, and k is the number of populated (at room T) conformations. The diagonal elements aii and off-diagonal elements for near-neighbor chemically bonded atoms aij are parameters of electronic structure, while the remaining off-diagonal matrix elements aij* are equal to the interatomic distances between nonbonded atoms i and j. The ECMC for all the compounds under consideration should be compared in order to reveal those matrix elements which, within a given accuracy, are common for all the active compounds and not present in the same combination in the inactive ones. In this way a smaller number of matrix elements can be separated forming a sub-matrix, the EC sub-matrix of activity (ECSA), that describes the electronic and conformational parameters required for the activity under consideration, the Ph.

The presence of the Ph is a necessary but not sufficient condition of activity. The latter is essentially influenced by the APS which can be defined as additional groups of atoms that produce steric restrictions or competing charges (reactivities) which restrain the proper docking of the Ph with the bioreceptor and hence diminish the activity, partially or completely. In the APS module, APS influence on the activity is parameterized using the whole trial set. The general formula below gives the activity A as a function of the presence of Ph and APS parameters di and h (distances), a i, g ij, (angles) and a set of constants k ij chosen to minimize the difference between the calculated and experimental activities of the trial set:

, where

This formula is then used to predict the activity of other compounds. The method is demonstrated for rice blast activity with a prediction power of ~90%.

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