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image of Molecular Dynamics and Energetic Insights into Novel PARP15 Inhibitors: A Structural Approach for Targeting BRCA-Mutated Breast Cancer

Abstract

Introduction

Breast cancer remains a critical global health issue, particularly in patients with BRCA1/2 mutations, which lead to genomic instability and increased cancer susceptibility. While PARP inhibitors targeting PARP1 and PARP2 have shown clinical success through synthetic lethality, PARP15, a mono-ADP-ribosyltransferase involved in DNA repair and tumour progression, remains largely understudied.

Methods

A structure-based virtual screening approach was applied to identify potential PARP15 inhibitors. The screening was performed on a Bioactive Screening Compound Library consisting of over 12,200 drug-like small molecules. Using the MTiOpenScreen platform, 1,500 candidate compounds were initially shortlisted. Molecular docking was then conducted to identify top-binding compounds, followed by 500-nanosecond molecular dynamics simulations to assess complex stability. Principal component analysis (PCA), free energy landscape (FEL) evaluation, and absorption, distribution, metabolism, and excretion (ADME) profiling were also performed to characterise compound behaviour and drug-likeness.

Results

Three compounds, F2002-0551, F2028-0309, and F1495-1822, emerged with docking scores surpassing the known PARP15 inhibitor, Niraparib. Molecular dynamics simulations confirmed their structural stability with low RMSD values and favourable FELs. PCA revealed consistent ligand dynamics, and ADME analysis showed high gastrointestinal absorption and other drug-like characteristics. Superimposition analysis demonstrated minimal deviation in docked poses, indicating strong and stable interactions with PARP15.

Discussion

These results highlight the therapeutic potential of the selected compounds as novel PARP15 inhibitors. Their favourable binding stability and pharmacokinetic profiles support their candidacy for further development against BRCA-mutated breast cancer.

Conclusion

F2002-0551, F2028-0309, and F1495-1822 represent promising leads for PARP15 inhibition. This study offers a computational foundation for future experimental validation and therapeutic exploration in BRCA-associated breast cancer.

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2025-11-04
2026-03-02

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Molecular Dynamics and Energetic Insights into Novel PARP15 Inhibitors: A Structural Approach for Targeting BRCA-Mutated Breast Cancer
Bentham Science Publishers ; https://doi.org/10.2174/0113816128395302251006180024
/content/journals/cpd/10.2174/0113816128395302251006180024
/content/journals/cpd/10.2174/0113816128395302251006180024
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  • Article Type:     Research Article
Keywords: free energy landscape ; BRCA-mutated breast cancer ; DNA ; molecular dynamics simulations ; PARP15 inhibitors ; ADME

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