Supplementary Materials

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 according to anti-cancer activity and the rule of three and then docked. The fragment with the highest affinity then underwent fragment growing. Resulting candidate drugs were then docked and screened for toxicity. Qualitative structure-activity relationship analysis was conducted to determine the properties relevant to the affinities. 4 distinct chemical domains were determined, candidates retaining the base structure provided both anticancer potential due to their substructures as well as additional interactions with residues due to the increase in size and chemical 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.