Cresset’s fundamental 3D ligand similarity technology compares molecules in terms of their molecular electrostatic interaction potentials (MIPs), or ‘fields’. The MIP of a molecule is a scalar field where the value at each point in space is the interaction energy of a charged probe atom (with the van der Waals parameters of oxygen) with the molecule. These are calculated using the XED force field. As the interaction energies are poorly defined inside the molecule, the field value is set to zero anywhere where the van der Waals interaction energy is positive and larger than the absolute value of the electrostatic energy.
Dealing with a full 3D scalar potential is computationally difficult. You can sample the values on a grid, but you then have issues with gauge variance, grid spacing and so forth leading to irreproducibility. Instead, what Cresset does is ask “Where are the maxima/minima of the fields?”. Each such extremum is termed a ‘field point’, and the set of field points is uniquely defined for any given molecular conformation. The field points are usually displayed as colored spheres, where the visual extent of each field point is determined by the magnitude of the field – stronger fields get larger spheres. This allows you to see at a glance where the molecule can make a locally maximal electrostatic interaction with another molecule. Full definitions of the fields and algorithm used to compute the field point positions are detailed in the paper Molecular Field Extrema as Descriptors of Biological Activity: Definition and Validation.
Cresset’s fields have been validated as part of the development of the the XED force field, and have also been extensively compared to experimental data from small molecule crystal structures. The distribution of H-bond donors and acceptors around a functional group is a good proxy for the interaction potential, and the field point patterns obtained are consistent with this information. Fields are also particularly useful for describing the properties of aromatic systems (building on the XED force field’s excellent description of these): the field surface around an aromatic ring holds a wealth of information about how electron rich/poor it is, how its charge density is arranged, and how strong a π-stacking interaction it could make. A few example rings are shown below.
Whenever you are describing molecules in terms of electrostatics, it is critical to handle formal charge states correctly. Cresset have a complex rule-based system for assigning formal charges which, while not a complete pKa estimator, will correctly assign the protonation state for the vast majority of drug-like molecules at pH 7. However, just assigning the formal charge state is not enough. Solvation is much more important for ions than for neutral molecules, so additional effort needs to be made to account for that. We have developed a charge scaling algorithm which allows for meaningful comparisons between molecules with different formal charges, while retaining the speed of calculation.