Elucidating the Dynamics and Selective Mechanistic Mode of Inhibition of a Novel Poly ADP-Ribose Polymerase-1 Inhibitor

Aims: To expound the mechanisms of selective PARP-1 inhibition by compound10n. Background: Poly ADP-ribose polymerase-1 (PARP-1), due to its role in DNA damage and repair, has been identified as a crucial therapeutic target to attenuate cancer development and progression Objective: Selective inhibition has remained a focal point in PARP-1 targeting, therefore, we explored the selective inhibitory mechanism of Compound10n. Methods: we employed computational methods for this study. Results: Findings revealed that the inhibitor stabilized the characteristic motion of activated PARP-1 as evidenced by reductions in residual deviations and structural flexibility. Findings further revealed that compound10n was favorably bound at the active site PARP-1 as supported by the occurrence of strong hydrogen and halogen bonds based on complementarity. These were in addition to aromatic bonds with enhanced ring to ring stability. Steady and high-affinity interactions between the fluorine atom of compound10n and Glu988 could potentiate the selective activity of the compound. Interaction analyses also revealed that inhibitor binding was strongly dependent on electrostatic effects over van der Waal contributions which were relatively minimal. Conclusion: We believe findings from this study will further contribute to the rational structure-based design of highly selective PARP-1 inhibitors.