We then tested the approach on a larger dataset of 16 ligands binding to MALT1 (Mucosa-associated lymphoid tissue lymphoma translocation protein 1). The ligands mostly differ by small R-group changes, however, there are a few ring formation transformations (isopropyl to cyclopropyl) and one stereo inversion transformation (see SI Figure ) that can pose challenges in standard RBFE if the chimeric molecule (the molecule that is composed of atoms to represent both ligands) is not created carefully.