Molecular Dynamics and Energetic Insights into Novel PARP15 Inhibitors: A Structural Approach for Targeting...

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.