5 research outputs found
Simulation of Metal–Ligand Self-Assembly into Spherical Complex M<sub>6</sub>L<sub>8</sub>
Molecular dynamics simulations were performed to study
the self-assembly
of a spherical complex through metal–ligand coordination interactions.
M<sub>6</sub>L<sub>8</sub>, 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 M<sub>6</sub>L<sub>8</sub> 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 M<sub>6</sub>L<sub>8</sub> nanospheres is crucially important
in their supramolecular self-assembly
Coordination-Directed Self-Assembly of M<sub>12</sub>L<sub>24</sub> Nanocage: Effects of Kinetic Trapping on the Assembly Process
We demonstrate the spontaneous formation of spherical complex M<sub>12</sub>L<sub>24</sub>, which is composed of 12 palladium ions and 24 bidentate ligands, by molecular dynamics simulations. In contrast to our previous study on the smaller M<sub>6</sub>L<sub>8</sub> cage, we found that the larger M<sub>12</sub>L<sub>24</sub> self-assembly process involves noticeable kinetic trapping at lower nuclearity complexes, <i>e.g.</i>, M<sub>6</sub>L<sub>12</sub>, M<sub>8</sub>L<sub>16</sub>, and M<sub>9</sub>L<sub>18</sub>. 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 M<sub>12</sub>L<sub>24</sub> 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-3Â(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-2Â(1<i>H</i>)-one, to fill this subpocket with the aid of complex structure
information. 3-Hydroxy-5-(2-phenylethyl)Âpyridine-2Â(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-3Â(2<i>H</i>)-one derivatives, which are equivalent to the 3-hydroxy-pyridine-2Â(1<i>H</i>)-one series but lack cell toxicity. 6-[2-(3,5-Difluorophenyl)Âethyl]-4-hydroxypyridazin-3Â(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