De novo generation of molecular structures using optimization to select graphs on a given lattice

A recurrent problem in organic chemistry is the generation of new molecular structures that conform to some predetermined set of structural constraints that are imposed in an endeavor to build certain required properties into the newly generated structure. An example of this is the pharmacophore model, used in medicinal chemistry to guide de novo design or selection of suitable structures from compound databases. We propose here a method that efficiently links up a selected number of required atom positions while at the same time directing the emergent molecular skeleton to avoid forbidden positions. The linkage process takes place on a lattice whose unit step length and overall geometry is designed to match typical architectures of organic molecules. We use an optimization method to select from the many different graphs possible. The approach is demonstrated in an example where crystal structures of the same (in this case rigid) ligand complexed with different proteins are available.