A Theoretical Study of the Interaction of PARP-1 with Natural and Synthetic Inhibitors: Advances in the Therapy of Triple-Negative Breast Cancer

Abstract

In the current study, we have investigated the secondary metabolites present in ethnomedical plants used for medicinal purposes-Astilbe chinensis (EK1), Scutellaria barbata D. Don (EK2), Uncaria rhynchophylla (EK3), Fallugia paradoxa (EK4), and Curcuma zedoaria (Christm.) Thread (EK5)-and we have compared them with five compounds of synthetic origin for the inhibition of PARP-1, which is linked to abnormal DNA replication, generating carcinogenic cells. We have studied these interactions through molecular dynamics simulations of each interacting system under physiological conditions (pH, temperature, and pressure) and determined that the compounds of natural origin have a capacity to inhibit PARP-1 (Poly(ADP-ribose) Polymerase 1) in all the cases inspected in this investigation. However, it is essential to mention that their interaction energy is relatively lower compared to that of compounds of synthetic origin. Given that binding energy is mandatory for the generation of a scale or classification of which is the best interacting agent, we can say that we assume that compounds of natural origin, having a complexation affinity with PARP-1, induce cell apoptosis, a potential route for the prevention of the proliferation of carcinogenic cells.

Keywords: PARP-1; docking; molecular dynamics simulation; molecular mechanics.

Figure 1

Structure of the PARP-1 protein obtained from the PDB server, ID: 4DQY.

Figure 2

Initial secondary structure of PARP-1 (ID: 4DQY), without additional structural agents used for crystallization.

Figure 3

Analysis of structural parameters RMSD, RMSF, and Rg of PARP-1 after 500 ns of molecular dynamics simulation.

Figure 4

Ramachandran diagram analysis of PAR-$ after the 500 ns simulation.

Figure 5

Two-dimensional structure of inhibitors of synthetic origin.

Figure 6

Two-dimensional structure of inhibitors of natural origin.

Figure 7

(a) Final structure of the PARP-1—DK1 coupled system after conducting a molecular dynamics simulation. (b) LigPlot diagram of the interaction.

Figure 8

(a) Final structure of the PARP-1—EK2 coupled system after conducting a molecular dynamics simulation. (b) LigPlot diagram of the interaction.

Figure 9

RMSD for the tnteraction of PARP-1 with synthetic origin compounds.

Figure 10

RMSD for the interaction of PARP-1 with natural origin compounds.

Figure 11

Ramachandran plots showing the conformational states of PARP$$ when interacting with different compounds. (a) Interaction with DK1. (b) Interaction with EK2.