From tortoise-shell-like molecular segments to C(4n)H(2n)N(2n) (n = 3-8) cages stabilized by alkenyl: a theoretical study.

The C(4n)H(2n)N(2n) (n = 3-8) cage molecules with D(nh) symmetry and their nitrated products, C(4n)N(4n)O(4n) (n = 3, 4, 5) and C(4n)H(n)N(3n)O(2n) (n = 4, 6, 8) were studied by DFT at the B3LYP/cc-pVDZ level. Their geometrical structures, ground-state energies, and heats of formation have been investigated. They exhibit an obvious cage effect. Hirshfeld partitioning charges in momentum space give evidence of high strained energy in the title compounds. Their orbital energy and frontier orbital shape and electrostatic potential calculation are also studied. Investigation of heat of formation and NICS analysis reveal that C(24)H(12)N(12) is the most stable molecule among title compounds with D(nh) symmetry. Their half nitrated products are predicted as a promising candidate for high energy matter.

Structure and relative stability of drum-like C4nN2n n = 3-8) cages and their hydrogenated products C4nH4nN2n (n = 3-8) cages.

The drum-like C4nNn (n = 3-8) cages and corresponding hydrogenated products C4n H4nN2n (n = 3-8) are studied at the DFT B3LYP/6-31G** level. Their structures, energies, and vibrational frequencies have been investigated. Comparison of heat of formation reveals that C32N16 with D8h symmetry in the C4nN2n (n = 3-8) series is a promising candidate as high energy density matter. The calculation of the DeltaG and DeltaH for the hydrogenation of C4nN2n (n = 3-8) shows that it is an exothermic reaction at 298 K and the C4nH4nN2n (n = 3-8) species are more stable than C4nN2n (n = 3-8) species. The analysis of molecular orbital and selected bond lengths of N-N and C-C provides another insight about their stability. Combined with the nucleus-independent chemical shifts (NICS) calculation, it is indicated that molecular stability for cage-shaped molecules depends on not only aromatic character but also the cage effect.

Molecular dynamics simulation study for LRH-1: interaction with fragments of SHP and function of phospholipid ligand.

The liver receptor homolog-1 (LRH-1) is an important transcriptional factor in the process of cholesterol and bile acids metabolism. In this article, molecular dynamics simulation for six systems with total 60 ns is employed to study LRH-1. LRH-1/phospholipid and LRH-1/SHP (fragments) interactions are analyzed by counting atomic contact number, identifying hydrogen bonds, and estimating binding free energies (by MM-PB/SA and N-mode analysis). Through integrating our modeling result with previous experimental data, deeper understandings to LRH-1/SHP interaction are obtained, and functions of the phospholipid ligand in LRH-1 are proposed.

3D-QSAR studies with the aid of molecular docking for a series of non-steroidal FXR agonists.

The farnesoid x receptor (FXR) has become a potential drug target for treating cholesterol-related and bile acid-related diseases recently. In this paper, 3-dimensional quantitative structure-activity (structure-affinity and structure-efficacy) relationships are investigated for a series of non-steroidal agonists (fexaramine series) by using the comparative molecular field analysis (CoMFA), where molecular docking method (FlexX) is employed to construct molecular superimposition maps. A proposal to design some new agonists is discussed lastly.

Recognition of LXXLL by ligand binding domain of the Farnesoid X receptor in molecular dynamics simulation.

The Farnesoid X receptor (FXR) has recently become a potential therapeutical target. The recruitment of coactivator protein (specified by LXXLL sequence) is the initial step in transcriptional activation of nuclear receptors (NRs). In this paper, the process of recognition of the LXXLL motif by the ligand binding domain (LBD) of FXR is observed in a 25 ns molecular dynamics simulation. The hydrophobic and hydrogen bonding interactions between the LBD and the coactivator are fully analyzed. This observation provides justification for the 'on deck' model proposed by Nettles and Greene. At last, insight to the protein-polypeptide interactions and protein conformational changes are discussed.

Fluoro-substitution effects in deoxyfluoro-D-glucose derivatives: random conformational search and quantum chemical calculation.

The effect of substitution by the fluorine atom at different positions of D-glucose was investigated by quantum chemical calculation of the low-energy conformers. These were obtained through the Random conformational search method. The geometries of conformers were optimized at the RHF/6-31(d) level, then reoptimization and vibrational analysis were performed at the B3LYP/6-31+G(d) level. Single-point energies were calculated at the B3LYP/6-311++G(2d,2p) level. The free energies of solvation in water were calculated utilizing the AM1-SM5.4 solvation model. For all substitution positions, the ring conformation does not change much, and the pyranoid 4C1 conformers are dominant, while variations in the substitution site result in different effects in the network of hydrogen bonds, anomeric effect, the solvation free energy, and the ratio of alpha- and beta-anomers.

Molecular Dynamics Simulation of Iminosugar Inhibitor-Glycosidase Complex: Insight into the Binding Mechanism of 1-Deoxynojirimycin and Isofagomine toward ß-Glucosidase.

The binding mechanism of iminosugar inhibitor 1-deoxynojirimycin and isofagomine toward ß-glucosidase was studied with nanosecond time scale molecular dynamics. Four different systems were analyzed according to the different protonated states of inhibitor and enzyme (acid/base carboxyl group, Glu166). The simulations gained quite a reasonable result according to the thermodynamic experimental fact. Further conclusions were made including the following: (1) 1-deoxynojirimycin binds with the ß-glucosidase as conjugate acid forms; (2) the slow onset inhibition of isofagomine aims to slow deprotonation of the acid/base carboxyl group which is caused by a nearly zero hydrogen bond interaction between the hydroxyls of the acid/base carboxyl group; and (3) the nucleophile carboxyl group plays an important role when the inhibitor binds with glucosidase.

A Direct Route to C-Vinylaziridines: Reaction of N-Sufonylimines with Allylic Ylides under Phase-Transfer Conditions or with Preformed Ylides at Low Temperature.

Allylic sulfonium salts 3, 5, 7, 11, 12, 13, and arsonium salt 14 react with aromatic, heteroaromatic, and alpha,beta-unsaturated N-sulfonylimines under solid-liquid phase-transfer conditions in the presence of KOH at room temperature to produce, respectively, vinyl-, (beta-phenylvinyl)-, and [beta-(trimethylsilyl)vinyl]aziridines in excellent yields within several minutes. In some cases, pyrroline compound 9 is obtained as a minor product. This aziridination reaction has also been carried out with preformed ylides, generated from sulfonium salts 3, 7, arsonium salt 14, and telluronium salts 15, 16 with a base in THF at -78 degrees C. In most examples, quantitative yields were achieved. However, the trans/cis selectivity of the reaction was not high in either case. A semistable allylic sulfonium ylide, i.e., dimethylsulfonium 3-(trimethylsilyl)allylide, was found to not undergo an expected [2,3]-sigma-rearrangement and so can also be used in this reaction.