Simulation of Metal–Ligand Self-Assembly into Spherical Complex M₆L₈

Molecular dynamics simulations were performed to study the self-assembly of a spherical complex through metal–ligand coordination interactions. M₆L₈, a nanosphere with six palladium ions and eight pyridine-capped tridentate ligands, was selected as a target system. We successfully observed the spontaneous formation of spherical shaped M₆L₈ cages over the course of our simulations, starting from random initial placement of the metals and ligands. To simulate spontaneous coordination bond formations and breaks, the cationic dummy atom method was employed to model nonbonded metal–ligand interactions. A coarse-grained solvent model was used to fill the gap between the time scale of the supramolecular self-assembly and that accessible by common molecular dynamics simulation. The simulated formation process occurred in the distinct three-stage (assembly, evolution, fixation) process that is well correlated with the experimental results. We found that the difference of the lifetime (or the ligand exchange rate) between the smaller-sized incomplete clusters and the completed M₆L₈ nanospheres is crucially important in their supramolecular self-assembly

Coordination-Directed Self-Assembly of M₁₂L₂₄ Nanocage: Effects of Kinetic Trapping on the Assembly Process

We demonstrate the spontaneous formation of spherical complex M₁₂L₂₄, which is composed of 12 palladium ions and 24 bidentate ligands, by molecular dynamics simulations. In contrast to our previous study on the smaller M₆L₈ cage, we found that the larger M₁₂L₂₄ self-assembly process involves noticeable kinetic trapping at lower nuclearity complexes, <i>e.g.</i>, M₆L₁₂, M₈L₁₆, and M₉L₁₈. We also found that the kinetic trapping behaviors sensitively depend on the bend angle of ligands and the metal–ligand binding strength. Our results show that these kinetic effects, that have generally been neglected, are important factor in self-assembly structure determination of larger complexes as M₁₂L₂₄ in this study

4‑Hydroxypyridazin-3(2<i>H</i>)‑one Derivatives as Novel d‑Amino Acid Oxidase Inhibitors

d-Amino acid oxidase (DAAO) catalyzes the oxidation of d-amino acids including d-serine, a coagonist of the <i>N</i>-methyl-d-aspartate receptor. We identified a series of 4-hydroxypyridazin-3­(2<i>H</i>)-one derivatives as novel DAAO inhibitors with high potency and substantial cell permeability using fragment-based drug design. Comparisons of complex structures deposited in the Protein Data Bank as well as those determined with in-house fragment hits revealed that a hydrophobic subpocket was formed perpendicular to the flavin ring by flipping Tyr224 in a ligand-dependent manner. We investigated the ability of the initial fragment hit, 3-hydroxy-pyridine-2­(1<i>H</i>)-one, to fill this subpocket with the aid of complex structure information. 3-Hydroxy-5-(2-phenylethyl)­pyridine-2­(1<i>H</i>)-one exhibited the predicted binding mode and demonstrated high inhibitory activity for human DAAO in enzyme- and cell-based assays. We further designed and synthesized 4-hydroxypyridazin-3­(2<i>H</i>)-one derivatives, which are equivalent to the 3-hydroxy-pyridine-2­(1<i>H</i>)-one series but lack cell toxicity. 6-[2-(3,5-Difluorophenyl)­ethyl]-4-hydroxypyridazin-3­(2<i>H</i>)-one was found to be effective against MK-801-induced cognitive deficit in the Y-maze

NMR Biochemical Assay for Oxidosqualene Cyclase: Evaluation of Inhibitor Activities on <i>Trypanosoma cruzi</i> and Human Enzymes

Oxidosqualene cyclase (OSC), a membrane-associated protein, is a key enzyme of sterol biosynthesis. Here we report a novel assay for OSC, involving reaction in aqueous solution, NMR quantification in organic solvent, and factor analysis of spectra. We evaluated one known and three novel inhibitors on OSC of <i>Trypanosoma cruzi</i>, a parasite causative of Chagas disease, and compared their effects on human OSC for selectivity. Among them, one novel inhibitor showed a significant parasiticidal activity

NMR Biochemical Assay for Oxidosqualene Cyclase: Evaluation of Inhibitor Activities on <i>Trypanosoma cruzi</i> and Human Enzymes

Oxidosqualene cyclase (OSC), a membrane-associated protein, is a key enzyme of sterol biosynthesis. Here we report a novel assay for OSC, involving reaction in aqueous solution, NMR quantification in organic solvent, and factor analysis of spectra. We evaluated one known and three novel inhibitors on OSC of <i>Trypanosoma cruzi</i>, a parasite causative of Chagas disease, and compared their effects on human OSC for selectivity. Among them, one novel inhibitor showed a significant parasiticidal activity