Structure-based identification of triazole-based PARP1 inhibitors: insights from docking and molecular dynamics...

Poly (ADP-ribose) polymerase 1 (PARP1) is a critical enzyme involved in DNA repair mechanisms, making it a promising target for anticancer drug development. Triazole derivatives have shown potential as PARP1 inhibitors, but systematic evaluation of a large library remains limited.

To perform comprehensive in silico screening and molecular dynamics simulations of 180 triazole derivatives to identify potent PARP1 inhibitors and evaluate their binding stability and interaction profiles.

A library of 180 triazole derivatives was subjected to molecular docking against the active site of PARP1 using [Schrodinger suite 2024-4]. Top-ranking compounds based on binding affinity were selected for further molecular dynamics (MD) simulations using to assess the stability of the ligand-protein complexes over a 100 ns simulation period. Binding free energies were calculated using MM-GBSA approaches. Key protein-ligand interactions were analyzed to elucidate binding mechanisms.

Docking results identified 10 triazole derivatives with superior binding affinities -9.4 to -5.5 kcal/mol compared to reference inhibitors. MD simulations confirmed stable binding conformations with root mean square deviation (RMSD) fluctuations within acceptable limits. Interaction analysis highlighted crucial hydrogen bonds and hydrophobic contacts with catalytic residues of PARP1.

The integrated in silico screening and molecular dynamics simulation approach successfully identified promising triazole derivatives as potential PARP1 inhibitors. These findings provide valuable insights for the rational design and optimization of novel anticancer agents targeting PARP1.