Molecular structure generation with substructure representations is provided. The computer-implemented method, comprises: selecting, by a device operatively coupled to a processor, a vertex in an existing graph of a molecular structure; replacing, by the device, the selected vertex with a sub-structure representation of a molecule, the sub-structure representation including two or more vertices; connecting, by the device, a new vertex to the sub-structure representation in the existing graph to generate a new graph; labeling, by the device, each of a plurality of vertices of the new graph by a canonical labeling method; and determining, by the device, whether a vertex that has a minimum label is the new vertex.