Theoretical insights into molecular mechanism and energy criteria of PARP-2 enzyme inhibition by benzimidazole analogues.

The emergence of poly (ADP-ribose) polymerase (PARP) inhibitors targeting a class of PARP enzymes has gained a great interest in cancer therapy. Majority of the PARP inhibitors are not isoform-selective which may cause unwanted off-target effects. In the present study, we explore the molecular mechanism and energy requirements for PARP-2 inhibition. This involves docking studies, frontier molecular orbital analysis, 500 ns molecular dynamics simulation (MD), binding free energy analysis and principal component analysis. The results clearly suggest the importance of hydrogen bonding (Gly429, Gln332, Ser470, Tyr455) and π-π stacking interactions (His428, Tyr455, Tyr462, Phe463, Tyr473) between residues and the inhibitor. Presence of lowest unoccupied molecular orbitals favors π-π stacking interactions and highest occupied molecular orbital orbital favors hydrogen-bonding interactions in the ligands. The stability of most active/PARP-2 complex is confirmed by hydrogen bonding and π-π stacking interaction parameters. Molecular-mechanics Poisson-Boltzmann surface area energy calculations showed that van der Waals and nonpolar solvation energy terms are crucial components for the stable binding of the ligands. Per residue analysis showed that tyrosine, histidine, and phenyl alanine residues are responsible for hydrophobic interactions with the ligands. Four new inhibitors are designed based on this study and the stability of PARP-2/inhibitor complex is validated by MD, density functional theory studies, and ADME/toxicity properties. Information from the present study can serve as a basis for designing new isoform-selective PARP-2 inhibitors.