Determination of Novel Hsp90 Inhibitors with In Silico Drug Repurposing Approach

Hyperactive Hsp90, which is overexpressed in cancer cells and causes accumulation of oncogenicrelated proteins that impair cellular homeostasis, has emerged as a therapeutic cancer target with

degradation of associated proteins induced by Hsp90 inhibition.

1

In addition, Hsp90 inhibitors have a

wide therapeutic window for cancer treatment, as the level of Hsp90 is distinctive between cancer

cells and normal cells. Overexpression of Hsp90 causes dysregulation of chaperone functions and

destroys cellular homeostasis, resulting in cell cycle acceleration, endless proliferation, and decreased

sensitivity to anti-growth signals that are characteristic of tumors.

2,3

In this study, a virtual screening

method was used to identify novel inhibitors of Hsp90 with these effects in mind.

In virtual screening, Hsp90 structure (PDB: 4W7T) was chosen as the receptor, all drugs in the Drugbank

database (~10767) were downloaded and were used as ligand. SP/XP hierarchical virtual screening

were performed to identify inhibitors targeting the Hsp90 protein in the screening process. Clusters

were created for drugs determined by screening using the Maestro Canvas Similarity and Clustering

program. These values were examined and hit molecules were determined. After, molecular dynamics

simulation studies (200 ns) were performed to analyze the dynamics between Hsp90-drug complexes.

System stabilities of the complexes was determined with RMSD and RMSF graphs and it was predicted

that they could be new Hsp90 inhibitors. In addition, this study can be supported by in vitro studies

and may lead to the design of potential new inhibitors.