In Silico Investigation of Potential PARP-1 Inhibitors from Traditional Chinese Medicine

Abstract

Poly(ADP-ribose) polymerases (PARPs) are nuclear enzymes which catalyze the poly-ADP-ribosylation involved in gene transcription, DNA damage repair, and cell-death signaling. As PARP-1 protein contains a DNA-binding domain, which can bind to DNA strand breaks and repair the damaged DNA over a low basal level, the inhibitors of poly(ADP-ribose) polymerase 1 (PARP-1) have been indicated as the agents treated for cancer. This study employed the compounds from TCM Database@Taiwan to identify the potential PARP-1 inhibitors from the vast repertoire of TCM compounds. The binding affinities of the potential TCM compounds were also predicted utilized several distinct scoring functions. Molecular dynamics simulations were performed to optimize the result of docking simulation and analyze the stability of interactions between protein and ligand. The top TCM candidates, isopraeroside IV, picrasidine M, and aurantiamide acetate, had higher potent binding affinities than control, A927929. They have stable H-bonds with residues Gly202 and, Ser243 as A927929 and stable H-bonds with residues Asp105, Tyr228, and His248 in the other side of the binding domain, which may strengthen and stabilize ligand inside the binding domain of PARP-1 protein. Hence, we propose isopraeroside IV and aurantiamide acetate as potential lead compounds for further study in drug development process with the PARP-1 protein.

Figure 1

Disordered protein predicted by PONDR-Fit and sequence alignment with disordered residues (yellow regions) and residues in the binding domain (magenta regions).

Figure 2

Chemical scaffolds of control and top three candidates.

Figure 3

Docking poses of PARP-1 protein complexes with A927929, isopraeroside IV, picrasidine M, and aurantiamide acetate.

Figure 4

Root-mean-square deviation and total energy over 40 ns MD simulation for PARP-1 protein complexes with A927929, isopraeroside IV, picrasidine M, and aurantiamide acetate.

Figure 5

Distance matrices consisting of the smallest distance between residue pairs for PARP-1 protein complexes with A927929, isopraeroside IV, picrasidine M, and aurantiamide acetate. Residues 1–348 in y-axis correspond to residues 2–349.

Figure 6

Secondary structure assignment and secondary structural feature ratio variations of each PARP-1 complex over 40 ns MD simulation. Residues 1–348 in y-axis correspond to residues 2–349.

Figure 7

Root-mean-square deviation value (upper left half) and graphical depiction of the clusters with cutoff of 0.105 nm (lower right half) for PARP-1 protein complexes with A927929, isopraeroside IV, picrasidine M, and aurantiamide acetate.

Figure 8

Docking poses of middle RMSD structure in the major cluster for PARP-1 protein complexes with A927929 (39.32 ns), isopraeroside IV (38.42 ns), picrasidine M (31.22 ns), and aurantiamide acetate (38.44 ns).

Figure 9

Distances of hydrogen bonds with common residues during 40 ns MD simulation. (a) A927929, (b) isopraeroside IV, (c) picrasidine M, and (d) aurantiamide acetate.