The presented ESP-Sim method uses the cheminformatics toolkit RDKit to generate different conformations of a molecule with (or without) a constrained anchor or core group, and computes shape and electrostatic potential similarities between pairs of conformers. Alternatively, ESP similarities can be computed on pre-aligned molecules. The electrostatic potential similarity is computed via the overlap integral of the Coulomb potentials of two molecules, as well as their respective self-overlap integrals as either Tanimoto or Carbo similarity. The Coulomb potential 𝑉(𝒓) describes the electric potential at a point 𝒓 as a sum of potentials of point charges 𝑞 𝑖 at points 𝒓 𝑖 as