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

Area of Science:

• Biochemistry
• Medicinal Chemistry
• Computational Chemistry

Background:

• Ubiquitin-specific protease 5 (USP5) is frequently found in malignant tumors.
• USP5 plays a role in stabilizing proteins that promote tumor progression.
• A need exists for potent USP5 inhibitors to target cancer development.

Purpose of the Study:

• To screen for and identify novel, effective inhibitors of USP5.
• To evaluate the potential of identified compounds as anti-cancer agents.

Main Methods:

• Screening of the TCMIO database for potential USP5 inhibitors.
• Utilizing molecular docking, molecular fingerprint analysis, quantum chemistry, and molecular dynamics simulations.
• Assessing binding affinity, molecular interactions, and ADMET properties.

Main Results:

• Three hit compounds (CHEMBL3645368, CHEMBL3689818, and CHEMBL2070208) were identified.
• These compounds demonstrated similar binding modes to a positive control.
• Computational analyses indicated superior binding energy and affinity compared to the positive control.
• Predicted ADMET profiles suggested low toxicity for the identified compounds.

Conclusions:

• CHEMBL3645368, CHEMBL3689818, and CHEMBL2070208 show significant potential for inhibiting USP5.
• These compounds represent promising candidates for further preclinical development as anti-cancer drugs targeting USP5.