Supplementary Materials for Manuscript

Clusterin is one of the proteins responsible for cancer chemoresistance, a prevalent issue in treatment. In this study, hot spot analysis showed a potential main ligand binding site and an allosteric site for facilitating protein-protein interactions. Potential inhibitors were designed through fragment-based drug discovery. Commercially available fragment libraries were screened for anti-cancer activity and the rule of three then docked. The highest affinity fragment underwent fragment growing. Resulting candidate drugs were docked and screened for toxicity. Qualitative structure-activity relationship analysis revealed chemical size and complexity being major contributors to binding affinity. Candidates retaining the base structure provided both anticancer potential and additional interactions with residues due to the increase in size and complexity. ADME filtering was conducted to filter out for general cancer cell application, the most favourable resulting in a top 1 final candidate drug precursor. Molecular dynamic simulations revealed good binding affinity in comparison with the reference ligand, highly suggesting potential for further optimization such as facilitating protein-protein interactions or as a drug delivery medium. Results of this study presents potential solutions to dealing with clusterin induced chemoresistance as well as other diseases that heavily involve clusterin.