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Unveiling Promising PARP12 Inhibitors through Virtual Screening for Cancer Therapy
Sara Seifeldin1, Mohd Saeed2, Hanan Ali Alatawi3
1Department of Clinical Laboratory Science, College of Applied Medical Science, University of Hail, Hail P.O. Box 2240, Saudi Arabia.
Background:
Poly (ADP-ribose) polymerase 12 (PARP12) plays a crucial role in DNA damage response (DDR) through DNA repair, maintaining genomic stability. Mutations in PARP12 contribute to genomic instability, leading to cancer progression. Targeting PARP12 mutants with small molecule inhibitors offers a promising therapeutic strategy.
Objective:
This study aims to identify potent inhibitors for PARP12 mutants using molecular docking-based virtual screening from the National Cancer Institute (NCI) compound library, followed by molecular dynamics (MD) simulations to validate binding stability.
Methods:
Homology models of human PARP12 mutants were developed for virtual screening. The topscoring compounds were refined through molecular docking, and their stability was analyzed using allatomistic MD simulations. Binding free energy (MMGBSA) calculations and structural dynamics assessments, including RMSD, RMSF, RoG, and SASA, were conducted to evaluate the drug-receptor interactions.
Results:
Three promising inhibitors, NCI-32743, NCI-32982, and NCI-659779, demonstrated high binding affinity and stability with PARP12 mutants. These compounds showed significant inhibitory potential, maintaining strong interactions with the target protein throughout the simulation period. ADMET and pharmacokinetic analyses confirmed their drug likeness and potential for further development.
Conclusion:
The identified inhibitors exhibit strong potential for targeting PARP12 mutants in cancer therapy. Further in vitro and in vivo studies are required to confirm their efficacy and therapeutic viability for clinical applications.
Insights
Researchers identified three potent small molecule inhibitors for Poly (ADP-ribose) polymerase 12 (PARP12) mutants. These compounds show promise for targeting cancer by stabilizing DNA damage response pathways.
Area of Science:
- Biochemistry
- Molecular Biology
- Pharmacology
Background:
- Poly (ADP-ribose) polymerase 12 (PARP12) is vital for DNA damage response (DDR) and genomic stability.
- PARP12 mutations are linked to genomic instability and cancer progression.
- Targeting mutant PARP12 with small molecule inhibitors presents a therapeutic opportunity.
Purpose of the Study:
- To identify potent inhibitors for PARP12 mutants.
- Utilized molecular docking and virtual screening of the NCI compound library.
- Validated inhibitor binding stability using molecular dynamics (MD) simulations.
Main Methods:
- Developed homology models of human PARP12 mutants for screening.
- Employed molecular docking to refine top-scoring compounds.
- Conducted all-atomistic MD simulations and MMGBSA calculations to assess binding stability and drug-receptor interactions.
Main Results:
- Identified three promising inhibitors: NCI-32743, NCI-32982, and NCI-659779.
- These compounds exhibited high binding affinity and stable interactions with PARP12 mutants.
- ADMET and pharmacokinetic analyses indicated favorable drug-like properties.
Conclusions:
- The identified inhibitors show significant potential for targeting PARP12 mutants in cancer therapy.
- Further in vitro and in vivo studies are warranted to confirm efficacy.
- These compounds represent viable candidates for clinical development against PARP12-mutated cancers.
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