Fields

It has long been known that compounds of different molecular structure can bind to the same protein site and elicit the same biological effect. This can be explained by considering the molecules' fields rather than their atomic structure, because the field pattern is a far superior description of a molecule's binding properties than its atomic structure. Compounds which are structurally diverse but show comparable activity have similar fields and hence similar binding properties.

Cresset uses the XED force field and calculates four fields to model binding:

The negative, positive and steric fields are derived from calculating the interaction energy between an appropriately charged probe atom and the molecule's surface. The hydrophobic field is a density function around hydrophobic atoms which has a maximum value at the centre of hydrophobic groups.

Cresset stores information about the molecular fields by calculating the positions and intensities of the fields at their local maxima: each field maximum is called a "field point". The set of field points for a molecule is a reasonably complete description of all of the strong binding interactions that that molecule could make.

Although our field points look superficially like traditional pharmacophores, they are far superior:

their positions are determined from the underlying physical properties of the molecule (rather than being placed by pattern matches on groups of atoms)
they encode size/strength information (as e.g. not all H-bond acceptors are equal)
our molecular comparison technology allows us to utilise the full analytical field of each molecule as well as the field point sizes and positions when calculating molecular similarities.

These advanced field-based descriptors allow us to undertake previously unviable tasks including ultra high throughput database searching of field similarity (using FieldPrints™ - a 1D vector representation of field point patterns), visual display and comparison of field properties (using field points) and optimised field superpositions (using the full field).

A molecule's field pattern depends on its conformation. Cresset has developed XedeX™ to map conformational space and produce a range of diverse conformations upon which fields can be added. Combining our field and XedeX™ technology allows us to:

Find new active chemotypes (hit-finding or lead switching) - FieldScreen™
Find the 3D bioactive conformation from known actives - FieldTemplater™
Align molecules input in 2D to a 3D field template created from an active molecule - FieldAlign™

Full details of the field technology can be found in Cheeseright et al. 2006