Computational insights into potent USP5 inhibitors based on multistep virtual screening and molecular dynamics simulation.

USP5 is widely distributed in various malignant tumors and can regulate the stability and promoting tumor progression of many tumor-related proteins. However, there is still a lack of highly active USP5 inhibitors. Therefore, effective inhibitors were screened in the TCMIO database in this study. Three hit compounds, CHEMBL3645368, CHEMBL3689818, and CHEMBL2070208, were finally obtained by molecular docking, molecular fingerprint, quantum chemistry, and molecular dynamics simulation. Molecular docking results showed hit compounds had similar binding mode comparing with positive compound. Quantum chemistry and molecular dynamics results showed hit compounds had better binding energy and higher affinity than the positive compound. ADMET predicted hit compounds had low toxicity. These results all suggest CHEMBL3645368, CHEMBL3689818, and CHEMBL2070208 may inhibit USP5 and could be candidates for further exploration.