Abstract 277: Discovery of promising antineoplastic drugs against the USP7 deubiquitinating enzyme: A pharmacophore-based FDA-approved and investigational drugs repurposing study

Abstract

Abstract The deubiquitinating enzyme ubiquitin-specific protease 7 (USP7) is a novel protein target for various hematological and solid-organ malignancies [1]. Its inhibition is thus considered a highly promising strategy for the development of new antineoplastic drugs. In this study, we applied an integrated approach with a major focus on pharmacophore modeling and screening combined with molecular dynamic simulations and free energy-based calculations to identify promising drugs as USP7-small molecule inhibitors. We started this drug repurposing study with the development of structure-based complex pharmacophore model hypotheses using the crystal structure of USP7. This pharmacophore modeling strategy was found to be most successful for the identification of promising molecules in drug discovery as we have recently reported [2]. We used three pharmacophore hypotheses to screen 6654 FDA-approved and investigational drugs as derived from the NPC's NIH library. Our pharmacophore screening led to the identification of 100 drugs that have well matched several chemical features of our hypotheses based on fitness scoring. All drugs were analyzed using 10-ns MD simulations and MM/GBSA system free energy. The 100 selected molecules encompassed over 35 different classes of drugs, among which antibiotics (13 identified), antivirals (6 identified) and anti-inflammatory drugs (5 identified) were the most represented. It is important to highlight that we found 4 antineoplastic drugs, suggesting potential interactions with the USP7 enzyme. Considering the important role of USP7 in cancer development and viral infections [3], we decided to further analyze all the discovered anticancer and antiviral drugs using 100-ns MD simulations. Additionally, we included the ten most stable molecules based on their system free energy (MM/GBSA scores lower than -69.0 kcal/mol) and all discovered anti-inflammatory drugs. In total, we ran 100-ns MD simulations for 24 molecules and a known USP7 inhibitor. Depending on this analysis, certain drugs will be tested in vitro to assess their level of USP7 inhibition. Our results thus far demonstrate the potential role of selected approved/investigational drugs as promising drugs that target USP7. These findings may open the route for efficient identification and characterization of promising USP7 inhibitors that could advance to clinical studies.