Figure outlines the main de novo design approaches compared in this study. Briefly, the design was carried out using ligand-based (alvaBuilder ) and structure-based (LigBuilder ) strategies. The fragments' sources were selected to represent similar starting points for both software despite differences in the fragmentation procedure. alvaBuilder requires chemical libraries as training sets for its fragmentation. Then, generated fragments are used as building blocks by the software. Each molecule selected from the training set is split into fragments following the Bemis and Murcko rules . In contrast, LigBuilder employs external fragment libraries provided by the user. In this study, fragment libraries were obtained using the fragmentation rules provided by the RECAP (Retrosynthetic Combinatorial Analysis Procedure) algorithm or fragment libraries that are commercially available.