Related Experiment Video
Updated: Jan 12, 2026
Assessment of Global DNA Double-Strand End Resection using BrdU-DNA Labeling coupled with Cell Cycle Discrimination Imaging
Published on: April 28, 2021
Molecular Dynamics and Energetic Insights into Novel PARP15 Inhibitors: A Structural Approach for Targeting
Badriyah Shadid Alotaibi1, Vivek Dhar Dwivedi2,3, Mohammad Amjad Kamal1,4,5
1Department of Pharmaceutical Sciences, College of Pharmacy, Princess Nourah bint Abdulrahman University, P.O. Box 84428, Riyadh, 11671, Saudi Arabia.
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 druglike 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.
Insights
Researchers identified three promising compounds (F2002-0551, F2028-0309, F1495-1822) as potential PARP15 inhibitors for BRCA-mutated breast cancer. These compounds show stable binding and favorable drug-like properties in computational studies.
Area of Science:
- Biochemistry
- Computational Chemistry
- Oncology
Background:
- Breast cancer, especially in BRCA1/2 mutation carriers, presents a significant health challenge due to genomic instability.
- PARP inhibitors (targeting PARP1/2) are effective, but PARP15, a key DNA repair enzyme, remains understudied.
- Targeting PARP15 offers a novel therapeutic strategy for BRCA-mutated cancers.
Purpose of the Study:
- To identify novel small molecule inhibitors of PARP15 using structure-based virtual screening.
- To evaluate the binding stability and drug-likeness of potential PARP15 inhibitors.
- To provide a computational basis for experimental validation of PARP15 inhibitors in BRCA-associated breast cancer.
Main Methods:
- Structure-based virtual screening of over 12,200 compounds against PARP15.
- Molecular docking, molecular dynamics simulations (500 ns), PCA, and FEL analysis.
- ADME profiling to assess pharmacokinetic properties and drug-likeness.
Main Results:
- Three compounds (F2002-0551, F2028-0309, F1495-1822) exhibited superior docking scores compared to Niraparib.
- Molecular dynamics simulations confirmed stable interactions and favorable binding free energies.
- ADME analysis indicated good gastrointestinal absorption and other favorable drug-like characteristics.
Conclusions:
- F2002-0551, F2028-0309, and F1495-1822 are promising lead compounds for PARP15 inhibition.
- These compounds demonstrate therapeutic potential for BRCA-mutated breast cancer.
- The study provides a computational foundation for further experimental investigation and drug development.
Related Concept Videos
02:57Targeted Cancer Therapies
There are several types of targeted therapies against...
02:37Restarting Stalled Replication Forks
03:03mTOR Signaling and Cancer Progression
The mTOR pathway or the...