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

Abstract

: 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. More so, selective inhibition has remained a focal point in PARP-1 targeting and has led to the development of numerous compounds, including the recently identified Cpd10n, a novel homoerythrina alkaloid derivative. To expound on the selective PARP-1 inhibition mechanisms by Cpd10n, we employed computational simulation methods in this study. 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 Cpd10n 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 an enhanced ring to ring stability. Steady and high-affinity interactions between the fluorine atom of Cpd10n 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. We believe findings from this study will further contribute to the rational structure-based design of highly selective PARP-1 inhibitors.