Targeting Ubiquitin-Specific Protease 7 (USP7): A Pharmacophore-Guided Drug Repurposing and Physics-Based Molecular Simulation Study

TL;DR

This study identifies potential new drugs that inhibit USP7, a protein linked to cancer progression, using computational methods and drug repurposing.

Contribution

A novel drug repurposing pipeline combining pharmacophore modeling and molecular simulations to identify USP7 inhibitors.

Findings

12 FDA-approved or investigational drugs were identified as promising USP7 inhibitors.

Molecular simulations and binding energy calculations validated the top hits.

The proposed inhibitors may overcome chemoresistance and improve cancer therapy.

Abstract

Ubiquitin-specific protease 7 (USP7) is a key regulator
of tumor
suppressors, oncoproteins, and epigenetic machinery, making it a compelling
target for cancer therapy. Overexpression of USP7 correlates with
worse survival of patients with multiple types of cancer, including
multiple myeloma, and has been shown to contribute to chemoresistance.
Here, we represent a structure-based drug repurposing pipeline to
identify novel USP7 inhibitors from a curated library of 6654 FDA-approved
and investigational small molecules. Using structure-based pharmacophore
models derived from USP7-ligand crystal structures, we screened and
prioritized hits based on pharmacophoric compatibility. The top 100
hits were subjected to short 10-ns molecular dynamics (MD) simulations
and MM/GBSA binding free energy calculations, narrowing down to 36
promising ligands. These were further evaluated through longer (100
ns) MD simulations, binding energy refinement, ligand clustering based
on molecular fingerprints, and cancer-specific activity predictions
using a binary QSAR model. By integrating our findings, we propose
12 drugs as the most promising lead molecules: carafiban, alnespirone,
morclofone, etofylline clofibrate, xantifibrate, cefmatilenum, cefovecin,
puromycin, troglitazone, droxicam, vidarabine, and furbucillin. Further
in vitro biological activity testing and validation of these potential
USP7 inhibitors may lead to the discovery of highly promising USP7
inhibitors as anticancer drugs.

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