A Novel Ligand-Mapping Method Based on Molecular Liquid Theory

The recent development of a novel ligand-mapping method is reviewed. The method is based on a statistical-mechanical molecular theory of solvation, known as the three-dimensional reference interaction site model (3D-RISM). In the 3D-RISM-based ligand mapping (3D-RISM-LM) method, using the all-atom model for a target protein immersed in a ligand-water mixture solvent, the 3D-spatial distributions of the ligand atomic sites around the protein are first obtained, and then the most probable binding modes of the ligand molecule are constructed from the distributions. Unlike conventional docking simulations, 3D-RISM-LM can incorporate the effect of water from the atomic to thermodynamic level into the binding affinity through statistical mechanics. It has been demonstrated that 3D-RISM-LM can sensitively detect even weak binding modes of small molecules over the entire surface of protein. Therefore, this approach is expected to be particularly useful in fragment-based drug design.