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Targeting Poly (ADP-ribose) polymerase-1 (PARP-1) for DNA repair mechanism through QSAR-based virtual screening and
Kun Cao1, Ruonan Wang2, Siyu Wu3,4
1Guangdong Provincial Key Laboratory of Medical Immunology and Molecular Diagnostics, The First Dongguan Affiliated Hospital, Guangdong Medical University, Dongguan, 523808, China. caokun@gdmu.edu.cn.
Abstract:
Poly (ADP-ribose) polymerase-1 (PARP-1) is a key enzyme in the base excision repair pathway, crucial for maintaining genomic stability by repairing DNA breaks. In cancers with mutations in DNA repair genes, such as BRCA1 and BRCA2, PARP-1 activity becomes essential for tumor cell survival, making it a promising target for therapeutic intervention. This study employs QSAR modeling, virtual screening, and molecular dynamics (MD) simulations to identify potential PARP-1 inhibitors. A dataset of inhibitors was analyzed using 12 molecular fingerprint descriptors to develop robust QSAR models, with the optimal model based on the CDK descriptor achieving R2 = 0.96, Q2_CV = 0.78, and Q2_Ext = 0.80. The model was applied to virtually screen three chemical libraries-ZINC, FDA, and NPA-identifying promising candidates for PARP-1 inhibition. Molecular docking revealed that compounds ZINC13132446, Z2037280227, and NPC193377 have strong binding affinity for the PARP-1 active site. MD simulations and MM-PBSA confirmed the stability of these complexes, with Z2037280227 and NPC193377 exhibiting the most stable interactions. These results underscore the potential of targeting PARP-1 as a therapeutic strategy for cancers with homologous recombination deficiencies, including prostate, breast, and ovarian cancer, particularly in patients with DNA repair deficiencies.
Insights
Researchers identified potential new cancer drugs targeting Poly (ADP-ribose) polymerase-1 (PARP-1), an enzyme crucial for DNA repair. Promising compounds were found using computational methods, offering new therapeutic strategies for cancers with DNA repair deficiencies.
Area of Science:
- Biochemistry and Molecular Biology
- Computational Chemistry
- Oncology
Background:
- Poly (ADP-ribose) polymerase-1 (PARP-1) is vital for DNA repair and genomic stability.
- PARP-1 inhibition is a promising therapeutic strategy for cancers with DNA repair gene mutations (e.g., BRCA1/2).
Purpose of the Study:
- To identify novel inhibitors of PARP-1 using computational approaches.
- To evaluate the binding affinity and stability of potential inhibitors with PARP-1.
Main Methods:
- Quantitative Structure-Activity Relationship (QSAR) modeling using molecular fingerprint descriptors.
- Virtual screening of chemical libraries (ZINC, FDA, NPA).
- Molecular docking, molecular dynamics (MD) simulations, and MM-PBSA calculations.
Main Results:
- Developed a robust QSAR model (R²=0.96, Q²_CV=0.78, Q²_Ext=0.80) for predicting PARP-1 inhibition.
- Identified ZINC13132446, Z2037280227, and NPC193377 as potential PARP-1 inhibitors with strong binding.
- MD simulations and MM-PBSA confirmed the stable interactions of Z2037280227 and NPC193377 with PARP-1.
Conclusions:
- Computational methods effectively identified potential PARP-1 inhibitors.
- Targeting PARP-1 offers a viable therapeutic avenue for homologous recombination-deficient cancers.
- Compounds Z2037280227 and NPC193377 show significant potential for further drug development.
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