Alignment of flexible molecules at their receptor site using 3D descriptors and Hi-PCA

Three categories of molecular flexibility are defined. A novel method of aligning partly flexible molecules with each other is described. The binding mode of one of these molecules to its receptor site was already well known from previous crystallographic studies, and this known binding mode was used to predict the binding mode of the other molecules at their receptor. The predictions were checked by comparison with previous observations, and were correct. Two novel methods were combined in this research. It was necessary to take account of the conformational changes which occur when each ligand molecule binds to the protein, and a new release of programme Grid was used for this. It was also necessary to analyse the Grid results in order to distinguish the role of each chemical group at the receptor site. This was done by applying hierarchical principal component analysis (Hi-PCA) methods to the descriptors obtained from Grid.