Synthesis and In Silico Evaluation of Piperazine-Substituted 2,3-Dichloro-5,8-dihydroxy-1,4-naphthoquinone Derivatives as Potential PARP-1 Inhibitors

Abstract

PARP-1 (poly(ADP-ribose)-polymerase 1) inhibitors are vital in synthetic lethality, primarily due to their specificity for PARP-1 over PARP-2 (PARP-1 > PARP-2). This specificity is crucial as it allows precise inhibition of PARP-1 in tumor cells with Breast Cancer 1 protein (BRCA1) or BRCA2 deficiencies. The development of highly specific PARP-1 inhibitors not only meets the therapeutic needs of tumor treatment but also has the potential to minimize the adverse effects associated with nonselective PARP-2 inhibition. In this study, a series of novel 2,3-dichloro-5,8-dihydroxy-1,4-naphthoquinone (DDNO) derivatives were synthesized, characterized, and evaluated regarding their PARP-1 inhibitory and cytotoxic activity. Compound 3 exhibited the highest cytotoxic potential against all cell lines, except for MDA-MB-231 cells. The inhibitory potential of these molecules against PARP-1 was evaluated through in silico molecular docking and molecular dynamics studies. Notably, compounds 5, 9, and 13 exhibited significant inhibitory activity in silico results, interacting with critical amino acids known to be important for PARP-1 inhibition during simulations. These compounds exhibited target-specific and strong binding profiles, with docking scores of -7.17, -7.41, and -7.37 kcal/mol, respectively, and MM/GBSA scores of -52.51, -43.77, and -62.87 kcal/mol, respectively. These novel compounds (DDNO derivatives) hold promise as potential PARP-1 inhibitors for the development of targeted therapeutics against cancer.

Figure 1

Synthetic pathway of piperazine-substituted 5,8-dihydroxy 1,4-naphthoquinone compounds.

Figure 2

Three-dimensional structure of the prepared PARP-1 protein (PDB ID: 7ONT) with the active region highlighted.

Figure 3

Three-dimensional ligand interaction diagram of compound 13 at the PARP-1 binding site.

Figure 4

(A) Analysis of the interactions between binding pocket residues of compound 13 throughout the MD simulations. (B) Two-dimensional ligand interaction diagram of compound 13 at the PARP-1 binding site. (C) Interaction percentages of residues in the binding pocket of PARP-1 with compound 13 during the MD simulations. The findings present statistical outcomes based on 100 trajectory frames collected over 10 ns MD simulations.

Figure 5

(A) Analysis of the interactions between binding pocket residues of Olaparib and PARP-1 throughout the MD simulations. (B) Two-dimensional ligand interaction diagram of Olaparib at the PARP-1 binding site. (C) Interaction percentages of residues in the binding pocket of PARP-1 with Olaparib during the MD simulations. The findings present statistical outcomes based on 100 trajectory frames collected over 10 ns MD simulations.