A novel Cu(II)-based DNA-intercalating agent: Structural and biological insights using biophysical and in silico techniques.

A new mixed-ligand Cu(II) complex formulated as [Cu(dipic)(amp)(H2O)].H2O (dipic: pyridine-2,6-dicarboxylic acid, amp: 2-amino-4-methylpyridine), was synthesized and structurally characterized by FTIR spectroscopy, CHN analysis, and the single-crystal X-ray crystallographic method. The complex crystallizes in an orthorhombic space group Pna21, and the coordination environment around the metal center was found to be a pentacoordinate CuN2O2OW distorted square-pyramidal geometry. In order to systematically explore a detailed in vitro and in silico study of the DNA binding of the title complex, various biophysical (UV-Vis absorption spectroscopy, fluorescence, competitive binding with ethidium bromide) and theoretical (DFT, molecular docking simulation, and QM/MM) methods were applied which revealed that the complex could intercalate with the insertion of the amp ligand between the DNA base pairs. The experimental thermodynamic parameters of the interaction revealed the spontaneity of the process and the domination of the hydrophobic interactions in the association and stabilization of the DNA-Cu(II) complex adduct, which was in line with the docking and QM/MM data. In vitro cytotoxic potential of the complex against the human breast adenocarcinoma (MCF-7) cells was examined using MTT assay, which indicated that cancerous cells showed inhibition in presence of the complex.

Study of tyramine-binding mechanism and insecticidal activity of oil extracted from Eucalyptus against Sitophilus oryzae.

The rice weevil, Sitophilus oryzae (L.), is a major pest of stored grains throughout the world, which causes quantitative and qualitative losses of food commodities. Eucalyptus essential oils (EOs) possess insecticidal and repellent properties, which make them a potential option for insect control in stored grains with environmentally friendly properties. In the current study, the binding mechanism of tyramine (TA) as a control compound has been investigated by funnel metadynamics (FM) simulation toward the homology model of tyramine1 receptor (TyrR) to explore its binding mode and key residues involved in the binding mechanism. EO compounds have been extracted from the leaf and flower part of Eucalyptus camaldulensis and characterized by GC/MS, and their effectiveness has been evaluated by molecular docking and conventional molecular dynamic (CMD) simulation toward the TyrR model. The FM results suggested that Asp114 followed by Asp80, Asn91, and Asn427 are crucial residues in the binding and the functioning of TA toward TyrR in Sitophilus Oryzae. The GC/MS analysis confirmed a total of 54 and 31 constituents in leaf and flower, respectively, where most of the components (29) are common in both groups. This analysis also revealed the significant concentration of Eucalyptus and α-pinene in leaves and flower EOs. The docking followed by CMD was performed to find the most effective compound in Eucalyptus EOs. In this regard, butanoic acid, 3-methyl-, 3-methyl butyl ester (B12) and 2-Octen-1-ol, 3,7-dimethyl- (B23) from leaf and trans- ß-Ocimene (G04) from flower showed the maximum dock score and binding free energy, making them the leading candidates to replace tyramine in TyrR. The MM-PB/GBSA and MD analysis proved that the B12 structure is the most effective compound in inhibition of TyrR.

Metamorphosis of prostate specific membrane antigen (PSMA) inhibitors.

Prostate-specific membrane antigen (PSMA), also called glutamate carboxypeptidase II (GCP(II)), is a Zn-dependent metalloprotease that is known as a well prostate cancer indication and a potential targeting towards anti-cancer medicines and drug delivery. Because of its centrality in the diagnostics and treatment of prostate cancer, several types of inhibitors are designed with particular scaffolds. In this study, important groups of related inhibitors as well as reported experimental and computational studies are being reviewed, in which we examined three functional groups on each group of structures. The importance of computational biochemistry and the necessity of extensive research in this area on PSMA and its effective ligands are recommended.

The influence of 5-fluorouracil anticancer drug on the DNA base pairs; a quantum chemical study.

In the present study, various hydrogen bonded complexes between five-fluorouracil (FU) with AT and GC base pairs were studied. First, to determine the affinity of different sites of the parent structures (FU, AT, and GC) for the hydrogen bond formation, their molecular electrostatic potentials are explored. The complexation energies and the strength of individual HBs of the plausible complexes were evaluated by energetic, geometric, spectroscopic, topologic, and molecular orbital descriptors. Our results reveal that, the FU-GC complexes (34.76-44.42 kcal mol-1) are more stable than the FU-AT ones (21.00-30.35 kcal mol-1). Among the complexes, the FU3-AT1 and FU3-GC3 are the most stable structures in the both series, which can be related to the sites with the highest affinity. Second, a detail analysis of the hydrogen bond descriptors were performed to elucidate the effect of FU on the strength of HB interactions within the base pairs. Interestingly, due to the formation of various interactions between the active sites of basic molecules, the strength of HB within the base pairs in the most cases increase about +2.75 and +.57 kcal mol-1 for the GC and AT nucleobases, respectively. Finally, several aromatic indices (HOMA, FLU, NICS (0) and NICS (1)) were applied to evaluate the significance of π-electron delocalization (π-ED) of 5/6 membered rings. These results clearly show that the π-ED of the benchmark systems increase with the formation or strengthening of the HB, which is in line with the resonance assisted hydrogen bond theory.