An Integrated in silico Approach and in vitro Study for the Discovery of Small‐Molecule USP7 Inhibitors as Potential Cancer Therapies

• DOI: 10.1002/cmdc.202000675
• Publication Date: 2020-10-16T14:20:29Z
• Authors: Duaa Kanan; Tarek Kanan; Berna Dogan; Muge Didem Orhan; Timucin Avsar; Serdar Durdagi
• Keywords: Docking (animal)

The ubiquitin-specific protease 7 (USP7) is a highly promising well-validated target for variety of malignancies. USP7 critical in regulating the tumor suppressor p53 along with numerous epigenetic modifiers and transcription factors. Previous studies showed that inhibitors led to increased levels anti-proliferative effects hematological solid cell lines. Thus, this study aimed identify potent safe hit as potential anti-cancer therapeutics via an integrated computational approach combines pharmacophore modeling, molecular docking, dynamics (MD) simulations post-MD free energy calculations. In study, crystal structure has been extensively investigated using combination three different chemical modeling approaches. We then screened ∼220.000 drug-like small molecule library ligands predicted be nontoxic were evaluated further. identified hits from each further examined by 1-ns short MD MM/GBSA analysis. total, we ran 1 ns 1137 selected on compounds. Based their average scores, 18 50 one inhibitor used positive control. vitro enzymatic inhibition assay testing our lead molecules confirmed these successful inhibition. Screening results within screening approaches, most was structure-based success rate 75 %. identification step closer finding appropriate effective therapies cancer. Our can scaffold structural optimization development, enabling research field.