A medicinal chemist would approach this challenge by seeking to understand how the different parts of a ligand's structure affect its activity at a target. This analysis of structureactivity relationships (SARs) is fundamental to understanding which properties of a molecule are essential for its activity, and hence being able to design novel molecules that have different structures but the same critical properties and predicted activity.
FieldView, a new tool from Cresset BMD, which is available for free, enables this type of SAR analysis. FieldView provides an intuitive way to gain insights into the required molecular properties and enables new molecules to be easily designed and their likely activity accurately evaluated.
To do this accurately from a biological perspective, FieldView uses molecular fields (Figure 1) rather than comparisons of 2-D structure. We know from years of drug discovery experience that a compound's biological activity cannot be predicted solely by its 2-D chemical structure. Biologists instinctively recognize that activity is instead determined by the interactions of the complementary molecular fields (surfaces) of the target protein with those of the ligand in their respective binding conformations. The interactions between these fields drive whether a ligand can make a good fit with the target's active site.
Field-based tools calculate and compare the field patterns of compounds to predict the similarity between their properties and activities. The most important regions of the fields (the extrema, where molecular interactions are likely to be strongest) are summarized by a field point pattern as shown by the colored spheres in Figure 1.
Since the target protein's active site conformation and (by extension) its fields have been highly constrained by evolution, any compound that is capable of presenting a complementary set of field points (in a 3-D conformation that is accessible under physiological conditions) is very likely to have the same biological activity and properties as the natural ligand.
This pattern of field points, therefore, becomes a template for the specific biological activity. As fields can be computed from the structures of active ligands alone, they can be used to identify diverse potential new lead structures even when the x-ray crystal structure of the target protein is not known.