Computational and synthetic approaches for the development of new agents in the management of oncological and neurodegenerative diseases

Given the crucial role of several proteins in regulating pathophysiological processes, the research work carried out during the PhD was focused on the canonical MUC1/CIN85 protein-protein interaction as well as on the aberrant aggregation of the neuronal protein α-synuclein. The above-mentioned targets might offer valuable tools for the developments of pharmacological treatments in cancer progression and neurological disorders. Moved by the purpose to identify new targets of pharmaceutical interest in cancer therapy, we focused our attention on the MUC1-CIN85 complex as a PPI implicated in the control of cancer progression and metastasis. For this reason, it was useful to start from the study of molecular contacts of MUC1 at CIN85 binding interface though a multi-computational approach, thus revealing new structural information relevant for the design of MUC1-CIN85 PPI inhibitors as potential anti-metastatic agents. In parallel, we investigated the role of amyloid aggregation of misfolded α-synuclein in the pathogenesis of Parkinson’s disease (PD). To date, inhibition of α-syn aggregation by small molecules has emerged as promising approach to block PD progression, thus providing new opportunities for drug discovery. Starting from previously identified α-syn aggregation inhibitors containing the chemotype 5-(4-pyridinyl)-1,2,4-triazole were optimized in terms of their in vivo efficacy. Our studies resulted in the identification of the ethyl 2-((4-amino-5-(pyridin-4-yl)-4H-1,2,4-triazol-3-yl)thio)acetate, that showed the ability to prevent MPTP-induced bradykinesia and to influence PD marker levels after administration of the same neurotoxin. In addition, we evaluated the prevention of the fibrillation process using light scattering and a Th-T binding assay; these compounds demonstrated a slight reduction in α-syn aggregation. To expand our knowledge about the chemical structural requirements exerting a blockade in the formation pf α-syn aggregates, we used the structures of two active α-syn inhibitors, SynuClean-D and ZPD-2, as query compounds for a ligand-based virtual screening (LBVS) on commercially available compound libraries using SwissSimilarity web-based tool. The selected compounds were analyzed in the Th-T fluorescence assay. Among them, the best active compound MeSC-4 displayed a similar inhibition profile compared to SynuClean-D and was used as a prototype for novel α-syn aggregation inhibitors. In addition, molecular modelling studies were performed to investigate the binding mode of MESC-4 through a consensus docking methodology.