Molecular Interaction and Inhibitory Potential of Polyphenol on DNA Repair Pathway in Small Cell Lung Cancer: A Computational Study

Abstract

Poly (ADP) ribose polymerase-1 (parp-1) is a ubiquitous and transient nucleoprotein with supra-function in orchestrating DNA damage repair symphony and has prognostic value in small cell lung cancer (SCLC). Accumulating evidence indicate that the substrate (NAD+) binding catalytic domain (active site) of this protein launches its activation. However, blocking this binding site is the key node in the inhibition of DNA repair pathway, thus signifying its importance in the control of small cell lung cancer progression. Approved drugs for the treatment of disease burden may stop the growth of the tumor cells by blocking some of the enzymes needed for cell growth or by killing the cells, stopping them from dividing via combinatorial efficacy. Clinical tractability of this strategy has been proven to potentially promote undesirable side effect. In the current study, our aim therefore, was to outsource a best in class small molecule inhibitor of PARP-1 from health-friendly source. We therefore, employed computational tools to investigate the therapeutic relevance of compounds from natural source as parp-1 inhibitor via molecular docking approach. 30 phyto-compounds were retrieved from the selected plant, +(-)gallocatechin GC (a polyphenolic compound) showed best binding affinity with the catalytic domain (active site) of parp-1 on comparism to the standard inhibitors. GC interact with the amino acid residue around the 4Ǻ of the catalytic domain (ASN-868, ASN-767, SER-864, GLY-863, HIS-862, TYR-896, PHE-897, TRP-861, ALA-898, SER-904, TYR-907, LYS-903) as evaluated by energy decomposition per residue of GC-parp-1 complex. The result from this investigation thus, project GC as a lead compound which may inhibit PARP-1 as a single therapy in the treatment of small cell lung cancer.

PARP-1-Associated Pathological Processes: Inhibition by Natural Polyphenols

“…This polyphenol is structurally similar to talazaparib, the strongest synthetic PARPi. Computer screening technologies also predict an existence of PARPi among polyphenols that may have affinities higher than clinically approved synthetic PARPi [ 112 ].…”

Investigations of Ni(II)Cysteine-Tyrosine Dithiocarbamate Complex: Synthesis, Characterization, Molecular Docking, Molecular Dynamic, and Anticancer Activity on MCF-7 Breast Cancer Cell Line

“…Additionally, careful and adequate ligand selection can improve the complexes’ active characteristics [ 6 ]. Dithiocarbamate complexes and other sulfur-containing ligands have been investigated as Zn metal-based chemotherapeutic drugs [ 33 ]. Sulfur donor ligands from the dithiocarbamate molecule are suited for and compatible with the majority of biological systems.…”