GRID force field interaction fields

The interaction of drug molecules with biological membranes is a three-dimensional (3D) recognition that is mediated by surface properties such as shape, Van der Waals forces, electrostatics, hydrogen bonding, and hydrophobicity. Therefore, the GRID force field [5-7], which is able to calculate energetically favorable interaction sites around a molecule, was selected to produce 3D molecular interaction fields. 

Carosati, E., Sciabola, S. and Cruciani, G. (2004) Hydrogen bonding interactions of covalently bonded fluorine atoms from crystallographic data to a new angular function in the GRID force field. Journal of Medicinal Chemistry, 47, 5114-5125. 

Cruciani et al., used a dynamic physicochemical interaction model to evaluate the interaction energies between a water probe and the hydrophilic and hydrophobic regions of the solute with the GRID force field. The VolSurf program was used to generate a PLS model able to predict log Poet [51] from the 3D molecular structure. 

One of the earliest decisions was to calibrate the GRID force field whenever possible by using experimental measurements rather than theoretical computations, and calorimetric measurements were therefore needed for the initial calibration in order to differentiate the enthalpic and entropic contributions to the overall free energy. However, only a very little calorimetric data was readily available at that time, about well characterised biological systems in which the structures of the interacting ligand and macromolecule were both known, and so a different approach was initially needed. 

E. Carosati, S. Sciabola, G. Cruciani, Hydrogen Bonding Interactions of Covalently Bonded Fluorine Atoms From Crystallographic Data to a New Angular Function in the GRID Force Field, J. Med. Chem. 2004, 47, 5114-5125. 

Atoms in molecules are first classified into different pharmacophoric types by the GRID force field parametrization. Features considered are hydrophobicity, hydrogen-bond donor and acceptor capabilities, and charge. Then, all accessible geometries for all the combinations of three or four features are calculated and encoded in the final vector. Fingerprints can be calculated both for ligands and proteins. In small ligands, pharmacophores are defined by triplets or quartets of atoms, vhich have critical interactions with a receptor. 

Figure 12.2 The X-ray structure of human UGT2B7 (left) showing the UDPGA-binding site (left), and their molecular interaction fields (right) obtained using GRID force field [21], showing the large cavity and the hydrophilic regions (in blue).

---