Introduction Poly ADP-ribose polymerase 1 (PARP-1) plays a crucial role in the gene repair process and thus attracts significant attention in the development of anti-cancer drugs. Although some FDA-approved compounds, including Olaparib, are effective in BRCA-mutated cancers, they face the obstacle of resistance and adverse reactions. Among these, Arenobufagin, a bufadienolide extracted from Bufo gargarizans, has been shown to be a potential PARP-1 inhibitor. Although the specific process of molecular inhibition is not fully understood, the investigation focused on the binding and molecular interactions between compound 30 and Olaparib to assesstheir potential as a novel PARP-1 inhibitory drug. Methods Molecular docking, molecular dynamics (MD) simulations, and molecular mechanics/generalized Born surface area (MM/GBSA) binding free energy (BFE) analyses were employed to explore the interactions between the ligands and the protein. Structural stability and key residues involved in the interactions mediated by the ligands were determined through conformational and per-residue energy decomposition (PRED) analyses. Results Arenobufagin 30 showed a binding affinity of –51.88 kcal/mol, which was similar to that of Olaparib (- 52.99 kcal/mol). This affinity was primarily supported by strong electrostatic and van der Waals interactions. Conformational analysis revealed that arenobufagin 30 induced specific dynamic changes in the PARP-1 molecule without disrupting its secondary structures. PRED showed improved binding with the crucial residues of the catalytic domain, suggesting an unusual mode of stabilization and inhibition. Discussion The similarity in binding affinity and unique conformational modification presented by arenobufagin 30 indicates an unconventional PARP-1 inhibitory mechanism. The atomistic information provided for the inhibitory actions of naturally occurring bufadienolides can be used to suggest their potential role in counteracting the limitations presented by existingPARP-1 inhibitors. Conclusion This study provides mechanistic insight into the inhibition of PARP-1 by Arenobufagin, suggesting it as a candidate for the development of novel anti-PARP-1 agents.
Kasumbwe et al. (Tue,) studied this question.