ABSTRACT
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.
ABSTRACT
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.
ABSTRACT
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.
Subject(s)
Computer Simulation , DNA-Binding Proteins/chemistry , Peptide Fragments/chemistry , Phospholipids/chemistry , Receptors, Cytoplasmic and Nuclear/chemistry , Transcription Factors/chemistry , Humans , Hydrogen Bonding , Molecular Conformation , Motion , Protein Binding , ThermodynamicsABSTRACT
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.
Subject(s)
Benzene Derivatives/chemistry , Computer Simulation , DNA-Binding Proteins/agonists , Quantitative Structure-Activity Relationship , Receptors, Cytoplasmic and Nuclear/agonists , Transcription Factors/agonists , Benzene Derivatives/pharmacology , Bile Acids and Salts/chemistry , Bile Acids and Salts/pharmacology , Drug Design , Humans , Models, Molecular , Molecular Structure , Protein BindingABSTRACT
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.
Subject(s)
Chemistry, Pharmaceutical/instrumentation , Chemistry, Pharmaceutical/methods , DNA-Binding Proteins/chemistry , Drug Design , Receptors, Cytoplasmic and Nuclear/chemistry , Transcription Factors/chemistry , Amino Acid Motifs , Computer Simulation , Crystallography, X-Ray , Humans , Hydrogen Bonding , Ligands , Models, Chemical , Molecular Conformation , Protein Binding , Protein Structure, Tertiary , Time Factors , Transcriptional ActivationABSTRACT
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.
Subject(s)
Deoxyglucose/chemistry , Fluorine/chemistry , Glucose/chemistry , Computer Simulation , Hydrocarbons, Fluorinated , Hydrogen Bonding , Models, Chemical , Models, Molecular , Molecular Conformation , Static Electricity , Stereoisomerism , ThermodynamicsABSTRACT
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.
ABSTRACT
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.