Binding profile of a mixed-ligand silver(I) complex with DNA and Topoisomerase I.

A new mixed-ligand Ag(I) complex, [Ag(daf)(phen)]NO3 (daf = 4,5-diazafluoren-9-one and dian = N-(4,5-diazafluoren-9-ylidene)aniline), was synthesized. The elemental analysis, FTIR, 1HNMR, UV-Vis spectroscopy, cyclic voltammetry, and DFT (Density Functional Theory) geometry optimization method were applied in order to predict the Ag(I) complex structure which concluded to a distorted tetrahedral N4 coordination around the Ag(I) center. A detailed in silico analysis of the bioaffinity of the complex to DNA and human DNA-Topoisomerase I was conducted using molecular docking simulations and ONIOM (Our own N-layered Integrated molecular Orbital and molecular Mechanics) techniques. In this overall scenario, the results suggest the dominance of π-π stacking interactions of the heteroaromatic ligands in the intercalating pocket of DNA and the active site of the enzyme and the rational correlation between being a good intercalator and a potent Topoisomerase I inhibitor. In vitro DNA-binding experiments by spectrophotometric, spectrofluorometric, Voltammetric, and viscometric techniques at physiological pH also confirmed the computational results. The complex inhibited MCF-7 cell growth in a dose-dependent manner while being nontoxic on HUVEC normal cells.

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.

On Calculating the Bending Modulus of Lipid Bilayer Membranes from Buckling Simulations.

The bending modulus is an important physical constant characterizing lipid membranes. Different methods have been devised for calculating the bending modulus from simulations, and one of them, named the buckling method, is nowadays widely used due to its simplicity and numerical stability. However, questions remain on the reproducibility, finite size effects, and interpretation of results on lipid mixtures. Here we explore the dependence of simulation results on the system size and the strain. We find that the dimensions of the box have a negligible impact on the results when the system size is beyond a certain threshold. We then calculate the bending rigidity for of a series of common single-component lipid bilayers (PC, PS, PE, PG, and SM), as well as a number of binary and ternary lipid mixtures. We find that bending moduli of lipid mixtures can be predicted from the weighted average of the moduli of the individual components, as long as the mixture is homogeneous. For phase-separated mixtures, the apparent elastic modulus is closer to the value of the softer component. Predictions of the bending modulus based on the area compressibility modulus are found to be generally unreliable.

Structural insights for rational design of new PIM-1 kinase inhibitors based on 3,5-disubstituted indole derivatives: An integrative computational approach.

Proviral integration Moloney virus (PIM) 1, 2, and 3 kinases are a family of constitutively active serine/threonine kinases that are involved in a number of signaling pathways important to cancer cells. Their overexpression in a variety of human hematopoietic malignancies and solid tumors suggest that inhibition of PIM signaling could provide patients with therapeutic benefit. In this study, a series of 3,5-disubstituted indole derivatives have been systematically studied using three-dimensional quantitative structure-activity relationship (3D-QSAR) analysis, molecular docking simulation, and partial least-squares (PLS) analysis methods to explore the influence of the structural characteristics on the inhibitory activity and use them to propose novel bioactive molecules. The comparative molecular field and comparative molecular similarity indices analyses (CoMFA and CoMSIA) models exhibited a good correlation between the predicted and experimental activities with excellent predictive capability and yielded statistically reliable value (CoMFA: Q2 = 0.535, R2 = 0.987, r2pred = 0.909; CoMSIA: Q2 = 0.785, R2 = 0.989, r2pred = 0.969). Based on the CoMFA and CoMSIA models and docking results, ten novel potent PIM-1 inhibitors (N1-N10) have been designed and the molecular models have validated their inhibitory activities. These results provided strong theoretical guidance for the development of novel PIM-1 inhibitors.

Binding interaction of a heteroleptic silver(I) complex with DNA: A joint experimental and computational study.

A new heteroleptic Ag(I) complex formulated as [Ag(daf)(phen)]NO3, where daf and phen stand for 4,5-diazafluoren-9-one and 1,10-phenanthroline, respectively, has been prepared and structurally characterized by elemental analysis, spectroscopic methods (IR, 1HNMR, and UV-Vis) and cyclic voltammetry. The geometry optimization around Ag(I) at the level of DFT has demonstrated that the Ag(I) center has been nested in a tetrahedral N4 coordination geometry which found to be in close agreement with the experimentally proposed structure. The bond lengths, angles, and the HOMO/LUMO energies have been calculated to substantiate the geometry of the complex. The DNA binding property of the Ag(I) complex has been explored in detail both theoretically (DFT and molecular docking) and experimentally (UV-Vis absorption spectroscopy, circular dichroism spectroscopy, luminescence quenching, competitive binding with ethidium bromide, cyclic voltammetry, and gel electrophoresis), indicating the good affinity of the Ag(I) complex for the intercalation (Kb (binding constant) = 3.45 × 105 M-1). Providing a fuller picture of Ag(I) complex-DNA interaction, the energy-minimized structure of the complex has been docked to the DNA with a d(AGACGTCT)2 sequence and the results are in close agreement with experimental achievements and make a deeper insight into the relationship between the structure and biological activity of the complex.

The effects of cation-π and anion-π interactions on halogen bonds in the [N⋯X⋯N]+ complexes: A comprehensive theoretical study.

The effects of ion-π interaction on the [N⋯X⋯N]+ halogen bond have been investigated by placement of monovalent ions on a pyridine ring plane of the complexes. The structural and electronic properties of the complexes have been studied via the density functional theory (DFT), quantum theory of atoms in molecules (QTAIM), non-covalent interaction (NCI) index and the nuclear magnetic resonance (NMR) calculations. The evaluation of halogen bonds in bis(pyridine)halonium complexes reveals the existence of two factors, ion-π interactions and intermolecular N─N distance, which play the important roles on the formation and stability of these quaternary complexes. The complexes are made via halogen bonding, where anti-cooperativity effect between two halogen bonds can be a reason for the change in quaternary complexes. The cation-π interaction decreases the total binding energy ǀΔEǀ, while anion-π interaction increases that. The trend in the ǀΔEǀ values are Ag+ < Au+ < Cu+ < py2X+ < Br-< Cl- < F- and is not changed by the methods of calculations. The spin-spin coupling constants 2XJN─N increase in the following order 15N⋯Cl+⋯15N > 15N⋯Br+⋯15N > 15N⋯I+⋯15N, as it similarly observes for the ǀΔEǀ and the cooperativity and synergetic energies (Ecoop and Esyn). According to AIM and NMR analysis, 1JN⋯X and 1XJN⋯X have opposite signs in closed and shared shell XBs. The obtained potential curves can be applied as valuable data to describe the effect of ion-π interaction on the improving of the three-center-four-electron [N⋯X⋯N]+ complexes reactivity.