The aim of our work is to develop an original molecular docking method using genetic algorithms (GA) based on simplified representations of the molecules. The representations are critical point graphs obtained by topological analysis of the electronic density of the molecules at medium crystallographic resolution (2.9 Å). We therefore used the XTAL and ORCRIT programs. In order to develop the docking method using critical point graphs, we chose the permethylated beta cyclodextrin and flurbiprofen complex and considered only steric interactions between the peaks. Flurbiprofen is chiral, so we studied R and S complexes. The GA we developed considers translations and rotations of the peak graphs of flurbiprofen into the cavity of the cyclodextrin, which is also represented by peaks and maintained fixed.
Out of the GA simulations, we chose four solutions which characterise the problem. They differ by the orientations and positions of the flurbiprofen into the cavity of the cyclodextrin. Minimisations through molecular mechanic have next been performed in order to validate the energies and explain the stability proposed by the GA. We therefore used the CVFF force field and Discover3. We have been able to show the importance of the van der Waals energies in comparison of the electrostatic ones. We also studied the influence of water because the cyclodextrin-R furbiprofen is hydrated, whereas the cyclodextrin- S flurbiprofen is not.