Ricerca tramite metodi di screening virtuale di un ligando per la β-catenina da includere in un degradatore

β-catenin is an important regulator of the Wnt/β-catenin pathway and alterations in the activity of this protein are responsible for different types of cancer (e.g. colorectal cancer, liver cancer and Chronic Lymphatic Leukaemia). β-catenin is found overexpressed in many cases, in these malignancies, provoking aberrant cell growth and deregulation of the cell cycle, with stimulation of some oncogenes such as c-Myc and cyclin-D. The development of a degrader (known also as PROTAC) offers the possibility to treat the disease correlated to an aberrant activity of the Wnt/β-catenin pathway. Degraders represent a new approach for the knockdown of target proteins within cells promoting protein degradation by matching protein with E3 ubiquitin ligases. The aim of the thesis is to find a small molecule able to bind (even without intrinsic activity) the β-catenin protein. The molecule will be used in the synthesis of a degrader as a warhead, the part of the degrader that bind β-catenin, the protein of interest (POI). The warhead was searched following the classical steps of a large-scale Drug Discovery process using tools that can be implemented in a laptop. Firstly, ZincPharmer tool was used to screen the ZINC database, a curated collection of commercially available chemical compounds. The hits were obtained in two different modes, named “Ligand Based” and “PocketQuery”, obtaining respectively the LB and the PQ pools of hits. Then, the selected pools of hits were further skimmed based on molecular properties relevant to ADME profile. Finally, a second selection was performed analyzing how the molecules interact with the target β-catenin (affinity and orientation) with two freely available docking tools (PatchDock and SwissDock). PatchDock and SwissDock performance was previously assessed by validating the two tools using five widely studied targets (COX1/2; TRPM8; Cav1.1; BCL2 and GABA(A)R). The validation of docking tools was performed by testing their ability in predict the pose of the ligand on the target and their capacity to calculate reliable affinity values.