Small molecule USP1 inhibitors from virtual screening as new cancer therapies
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Bethany Ma
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Ubiquitin-Specific Protease 1 (USP1) is a deubiquitinating enzyme that regulates DNA damage repair through the deubiquitination of key proteins, including PCNA and FANCD2-FANCI. USP1 supports DNA repair pathways that have been proven to be particularly important for the survival of certain cancer cells; So, its inhibition represents a promising strategy for developing new targeted cancer therapies. This study used a computational drug-discovery approach to identify potential small molecule USP1 inhibitors. Geometric and machine learning binding site prediction methods were used to identify and compare potential druggable pockets within USP1, resulting in the identification of several candidate binding sites. Pharmacophore modeling was then performed to characterize key molecular interactions within selected binding sites, including aromatic, hydrophobic, and hydrogen-bonding features. These pharmacophore models were used to screen compounds from the MCULE-ULTIMATE, Enamine, and MolPort chemical libraries, identifying 19 compounds with RMSD values below 0.2. The compounds were subsequently evaluated using SwissDock to assess predicted binding spontaneity, followed by SwissADME analysis to evaluate drug-likeness and Lipinski's Rule of Five and ProTox 3.0 analysis to assess predicted toxicity. Through this sequential screening process, MolPort-010-912-491 and Z1618187599 emerged as the most promising lead and backup compounds, respectively, based on their favorable docking results, low RMSD values, drug-like physicochemical properties, and predicted toxicity profiles. Overall, this study identified two potential USP1 inhibitors that warrant further investigation through molecular dynamics simulations, experimental binding assays, and in vitro cancer-cell testing.
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Bethany Ma
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References:
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