Insight into the binding of a synthetic nitro-flavone derivative with human poly (ADP-ribose) polymerase 1

A375 melanoma cells are sensitized to cisplatin-induced toxicity by a synthetic nitro-flavone derivative 2-(4-Nitrophenyl)-4H-chromen-4-one through inhibition of PARP1

“…ACPH, a potential anticancer agent with PARP1 inhibitory properties have been shown to potentiate the killing by cisplatin to make it effective at lower doses [5]. We have seen earlier that 4NCO can bind to the NAD + binding pocket of PARP1 enzyme to act as its inhibitor [7]. 4NCO exhibited limited toxicity in normal cells, but was effective in inducing killing in cancer cell lines and was most found to be most effective in A375 melanoma cells as obtained from our earlier ndings [34].…”

“…Molecular docking provides possible insight into the binding of any ligand to its receptor. The whole human PARP1 protein (PDB ID: 4DQY, resolution: 3.25 Å) was downloaded from https://www.rcsb.org/ as described earlier [7][18] [19]. The bound DNA structure was removed and the protein structure was re ned using the 'clean protein' tool in Discovery Studio (DS) 2.5 platform where the missing atom residues were added and waters were removed.…”

“…The bound DNA structure was removed and the protein structure was re ned using the 'clean protein' tool in Discovery Studio (DS) 2.5 platform where the missing atom residues were added and waters were removed. Energy minimization of the structure was then done using the 'energy minimization' protocol of DS 2.5 using Steepest Descent and Conjugate Gradient algorithms respectively applying the CHARMm force eld until the Root Mean Square Deviation (RMSD) reached a value of 0.001 kcal/mol/Å [7]. The stereochemistry of the energy minimized structure was checked using Ramachandran plot [20].The PDB structure of the DNA decamer containinig guanine-crosslinked adduct of cisplatin (PDB ID: 1A2E, resolution: 1.63 Å) was downloaded from https://www.rcsb.org/ [19][21].…”

“…From the modeling results obtained from HDOCK, NPDock and PatchDock, the best model of PARP1-cisplatin adduct DNA was selected and this was compared with the available PDB of DNA bound PARP1 (PDB ID: 4DQY). The ligand, 4NCO was prepared following our earlier works [7] [12]. The 3D structure of 4NCO was generated and optimized using the softwares Advanced Chemistry Development's/ ChemSketch [25] and PyMol 2.0 [26].…”

“…Several avones are also known to have PARP1 inhibitory activities [6], among them a synthetic avone derivative is 2-(4-Nitrophenyl)-4H-chromen-4-one (4NCO). From our earlier work based on in silico studies, we have observed that 4NCO could bind at the catalytic site of PARP1 thereby acting as a potent competitive inhibitor hindering the entry of nicotinamide adenine dinucleotide (NAD + ), the natural substrate of PARP1 [7]. 4NCO is a biologically potent avone derivative that also possesses anti-in ammatory, anxiolytic, antioxidant, antitumor and anti-metastatic activities and also known for its tyrosine kinase, BDZ receptor, CDK2, CK2, aldose reductase and DNA binding properties [8] [9][10] [11] [12].…”