Supplementary Materials for Manuscript

Numerous cancer treatments have been studied, however the concern of chemoresistance is still prevalent in the field, and one of the proteins responsible is clusterin. In this study, potential inhibitors of clusterin were designed through fragment-based drug discovery. Commercially available fragment libraries were screened for anti-cancer activity and the rule of three and then docked. The highest affinity fragment underwent fragment growing. Resulting candidate drugs were docked and screened for toxicity. Qualitative structure-activity relationship analysis was conducted to determine the properties relevant to the affinities, identifying 4 distinct chemical domains. Candidates retaining the base structure provided both anticancer potential and additional interactions with residues due to the increase in size and complexity, qualities found to contribute most to activity. 194 candidate drugs showed great potential for clusterin inhibition which could serve as inhibitors or as probes. ADMET filtering was conducted to filter out for general cancer cell application, the most favourable resulting in a top 1 final candidate drug that underwent molecular dynamics. Simulations revealed good initial binding affinity and significant ligand flexibility in the latter half of the 100ns simulation which highly suggest potential for further optimization such as facilitating protein-protein interactions or as potential drug delivery medium.