Here we present a new implementation of DeepFMPO utilizing a 3D-based molecular alignment method, where the ElectroStatic Potential (ESP) similarity between pairs of fragments is calculated. To this aim, we developed an open-source python package, ESP-Sim, which calculates the overlap integrals of the electrostatic potentials (generated from Coulomb potentials) of two molecules or fragments. Within DeepFMPO, the computation of ESP similarities can be broken down into six steps for each fragment pair (see Figure ) and is described in more detail below. Steps 2, 3 and 6 correspond to function calls of the ESP-Sim package, whereas steps 1 and 5 are innate to DeepFMPO. It is worth noting that this fragment alignment approach eliminates the challenging step of generating bioactive conformations for complete molecules, as well as alleviates the issue of aligning them correctly. Fragments that are similar are placed close to each other. The encoding of a fragment is determined by the path from the root to the leaf. Every branching to the left adds a "1" to the end of the encoding and a branching to the right adds a "0".