Unveiling Promising PARP12 Inhibitors through Virtual Screening for Cancer Therapy

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.