Conformational analysis of platinum antitumor drugs

Abstract

The purpose of this research is to effectively and efficiently search the conformational space of square planar Pt(II) antitumor drugs, using a combination of molecular mechanics, Monte Carlo (MC) and molecular dynamics (MD) methods. An MM2 force field for square planar Pt(II) complexes developed in our lab is extended to the related MM+ force field and shown to give equally reliable structural prediction. The reliability of the force field and three different conformational searching techniques (MC, MD and a random cartesian coordinate method (RCC)) are tested for cis-PtCl 2(NH 2R) 2 complexes. The MC and MD methods are found to be better than the RCC method for finding low-energy conformations. The conformational search results were used for a prototypical quantitative structure-activity relationship (QSAR) study and the results suggest that toxicity ( p( LD 50)) is reduced for complexes with larger volumes and surface areas. More importantly, the results show that molecular properties can be very geometry dependent, and hence an ensemble of low energy conformers must be considered for constructing QSARs for metal complexes with large and flexible ligands.