A PRIORI METHODS FOR POPULATION CONTROL WHEN USING THE MGAC METHOD FOR CRYSTAL STRUCTURE PREDICTION OF PHARMACEUTICAL DRUGS

D. GRILLO; M. B. FERRARO; ANITA ORENDT; J. C. FACELLI

TANDAR-CNEA

Congreso; VI Reunión Anula de la asocicion Argentina de Cristalografía; 2010

Asociación Argentina de Cristalografía

This poster presents recent advances in developing a priory scanning techniques to control the population of crystal structures when using genetic algorithms in crystal structure predictions (CSP). The authors have developed over that last ten years a powerful method to predict crystal structures using genetic algorithms (GA) and empirical potentials.1 The method has been applied to small molecules of pharmaceutical interest 2 and used to participate in the last three CSP blind tests organized by the Cambridge Crystallographic Data Center.3 The MGAC method uses the CHARMM program with the GAFF force field to calculate the crystal energies. Unfortunately, the empirical potential is prone to predict very low energies for non plausible structures that are far from the equilibrium; this is common artifact of empirical potentials that are parameterized to predict energies in the proximity of the energy minimum. Because the GA samples extensive regions of the configurational space, these structures are sometimes incorporated into the population. In recent studies of large pharmaceutical molecules they even dominated the population, to such extend that no physically possible structures resulted from the MGAC runs. A priori methods to preclude these bad structures to enter into the population appear a possible solution to the problem. The exclusion criteria should be easy to compute, to avoid performance degradation and it should be sufficiently accurate to avoid either false positives or negatives. Exclusion of the former ones leads to an artificial restriction of the search space and incorporation into the population of the second ones leads to poisoning of the population with bad structures. Here we present the preliminary results of using two different exclusion criteria, one based on the empirical computation of the crystal density and second based on the calculation of the direct atomic contacts. While the second method is computationally more expensive, it appears that it is more suitable for our purposes because the volume control approach produce excessive number of false positives. These approaches are being implemented in the MGAC code and will be tested in several pharmaceutical drugs for which MGAC has not been able to find good structures.