Free Energy Change of Micelle Formation for Sodium Dodecyl Sulfate from a Dispersed State in Solution to Complete Micelles along Its Aggregation Pathways Evaluated by Chemical Species Model Combined with Molecular Dynamics Calculations

Surfactant molecules, when dispersed in solution, have been shown to spontaneously form aggregates. Our previous studies on molecular dynamics(MD) calculations have shown that ionic sodium dodecyl sulfate molecules quickly aggregated even when the aggregation number is small. The aggregation rate, however, decreased for larger aggregation numbers. In addition, studies have shown that micelle formation was not completed even after a 100 ns-long MD run(Chem. Phys. Lett. 2016, 646, 36). Herein, we analyze the free energy change of micelle formation based on chemical species model combined with molecular dynamics calculations. First, the free energy landscape of the aggregation, ?G_(i+j)~+, where two aggregates with sizes i and j associate to form the(i + j)-mer, was investigated using the free energy of micelle formation of the i-mer, G_i~+, which was obtained through MD calculations. The calculated ?G_(i+j)~+ was negative for all the aggregations where the sum of DS ions in the two aggregates was 60 or less. From the viewpoint of chemical equilibrium, aggregation to the stable micelle is desired. Further, the free energy profile along possible aggregation pathways was investigated, starting from small aggregates and ending with the complete thermodynamically stable micelles in solution. The free energy profiles, G(l, k), of the aggregates at l-th aggregation path and k-th state were evaluated by the formation free energy ∑_in_i( l,k)G_i~+ and the free energy of mixing ∑_in_i( l,k)k_BTln( n_i( l,k)/n( l,k)), where ni(l, k) is the number of i-mer in the system at the l-th i aggregation path and k-th state, with n(l,k)= ∑_n_i( l,k). All the aggregation pathways were obtained from the initial i state of 12 pentamers to the stable micelle with i = 60. All the calculated G(l, k) values monotonically decreased with increasing k. This indicates that there are no free energy barriers along the pathways. Hence, the slowdown is not due to the thermodynamic stability of the aggregates, but rather the kinetics that inhibit the association of the fragments. The time required for a collision between aggregates, one of the kinetic factors, was evaluated using the fast passage time, t_(FPT). The calculated t_(FPT) was about 20 ns for the aggregates with N = 31. Therefore, if aggregation is a diffusion-controlled process, it should be completed within the 100 ns-simulation. However, aggregation does not occur due to the free energy barrier between the aggregates, that is, the repulsive force acting on them. This may be caused by electrostatic repulsions produced by the overlap of the electric double layers, which are formed by the negative charge of the hydrophilic groups and counter sodium ions on the surface of the aggregates.     

In silico fragment-mapping method: a new tool for fragment-based/structure-based drug discovery

Here, we propose an in silico fragment-mapping method as a potential tool for fragment-based/structure-based drug discovery (FBDD/SBDD). For this method, we created a database named Canonical Subsite–Fragment DataBase (CSFDB) and developed a knowledge-based fragment-mapping program, Fsubsite. CSFDB consists of various pairs of subsite–fragments derived from X-ray crystal structures of known protein–ligand complexes. Using three-dimensional similarity-matching between subsites on one protein and another, Fsubsite compares the surface of a target protein with all subsites in CSFDB. When a local topography similar to the subsite is found on the surface, Fsubsite places a fragment combined with the subsite in CSFDB on the target protein. For validation purposes, we applied the method to the apo-structure of cyclin-dependent kinase 2 (CDK2) and identified four compounds containing three mapped fragments that existed in the list of known inhibitors of CDK2. Next, the utility of our fragment-mapping method for fragment-growing was examined on the complex structure of tRNA-guanine transglycosylase with a small ligand. Fsubsite mapped appropriate fragments on the same position as the binding ligand or in the vicinity of the ligand. Finally, a 3D-pharmacophore model was constructed from the fragments mapped on the apo-structure of heat shock protein 90-α (HSP90α). Then, 3D pharmacophore-based virtual screening was carried out using a commercially available compound database. The resultant hit compounds were very similar to a known ligand of HSP90α. As a result of these findings, this in silico fragment-mapping method seems to be a useful tool for computational FBDD and SBDD.     

Miscibility of nifedipine and hydrophilic polymers as measured by (1)H-NMR spin-lattice relaxation

The miscibility of a drug with excipients in solid dispersions is considered to be one of the most important factors for preparation of stable amorphous solid dispersions. The purpose of the present study was to elucidate the feasibility of (1)H-NMR spin-lattice relaxation measurements to assess the miscibility of a drug with excipients. Solid dispersions of nifedipine with the hydrophilic polymers poly(vinylpyrrolidone) (PVP), hydroxypropylmethylcellulose (HPMC) and alpha,beta-poly(N-5-hydroxypentyl)-L-aspartamide (PHPA) with various weight ratios were prepared by spray drying, and the spin-lattice relaxation decay of the solid dispersions in a laboratory frame (T(1) decay) and in a rotating frame (T(1rho) decay) were measured. T(1rho) decay of nifedipine-PVP solid dispersions (3 : 7, 5 : 5 and 7 : 3) was describable with a mono-exponential equation, whereas T(1rho) decay of nifedipine-PHPA solid dispersions (3 : 7, 4 : 6 and 5 : 5) was describable with a bi-exponential equation. Because a mono-exponential T(1rho) decay indicates that the domain sizes of nifedipine and polymer in solid dispersion are less than several nm, it is speculated that nifedipine is miscible with PVP but not miscible with PHPA. All the nifedipine-PVP solid dispersions studied showed a single glass transition temperature (T(g)), whereas two glass transitions were observed for the nifedipine-PHPA solid dispersion (3 : 7), thus supporting the above speculation. For nifedipine-HPMC solid dispersions (3 : 7 and 5 : 5), the miscibility of nifedipine and HPMC could not be determined by DSC measurements due to the lack of obviously evident T(g). In contrast, (1)H-NMR spin-lattice relaxation measurements showed that nifedipine and HPMC are miscible, since T(1rho) decay of the solid dispersions (3 : 7, 5 : 5 and 7 : 3) was describable with a mono-exponential equation. These results indicate that (1)H-NMR spin-lattice relaxation measurements are useful for assessing the miscibility of a drug and an excipient in solid dispersions.     

Rapid and sensitive determination of tryptophan, serotonin and psychoactive tryptamines by thin-layer chromatography/fluorescence detection

A rapid, sensitive and selective method for the determination of tryptophan (Trp), serotonin (5-HT) and psychoactive tryptamines (PATs) by thin-layer chromatography (TLC) with fluorescence detection is proposed. These compounds form fluorophores on the developing plate by heating after spraying with sodium hypochlorite, hydrogen peroxide or potassium hexacyanoferrate(III)-sodium hydroxide reagent. Fluorescent spots (vivid blue) were observed by irradiation with ultraviolet light (365 nm). The detection limits of Trp, 5-HT and PATs were in the range from 0.01 microg to 0.06 microg. This method was effectively applied to the detection of confiscated PAT powder and PAT in abusers' urine samples.     

Evolution of Kondo resonance from a single impurity molecule to the two-dimensional lattice

The successive spectral evolution of the Kondo resonance state was investigated from a single iron(II) phthalocyanine molecule to the two-dimensional lattice on Au(111) by interrogating the individual molecules with a scanning tunneling microscope. A sharp Kondo peak appears in the single-impurity regime, which broadens and splits as the lattice builds up. The origin of spectral evolution together with the electronic ground state of the lattice are discussed based on the competition of the Kondo effect and Rudermann-Kittel-Kasuya-Yosida coupling between the molecular spins.     

UV LED lighting for automated crystal centring

A direct outcome of the exponential growth of macromolecular crystallography is the continuously increasing demand for synchrotron beam time, both from academic and industrial users. As more and more projects entail screening a profusion of sample crystals, fully automated procedures at every level of the experiments are being implemented at all synchrotron facilities. One of the major obstacles to achieving such automation lies in the sample recognition and centring in the X-ray beam. The capacity of UV light to specifically react with aromatic residues present in proteins or with DNA base pairs is at the basis of UV-assisted crystal centring. Although very efficient, a well known side effect of illuminating biological samples with strong UV sources is the damage induced on the irradiated samples. In the present study the effectiveness of a softer UV light for crystal centring by taking advantage of low-power light-emitting diode (LED) sources has been investigated. The use of UV LEDs represents a low-cost solution for crystal centring with high specificity.     

Synthesis of Rigid and Optically Active Bis(binaphthyl) Cyclic Compounds

Optically active cyclic bis(binaphthyl)s (4a–d), which are composed of aromatics, ethers, and ketonic carbonyls, were synthesized through a two‐step nucleophilic aromatic substitution reaction. Bis(binaphthyl) cyclic compounds (4a and 4b) were obtained in moderate yields when difluoride 3a and 3b were employed. On the other hand, bis(binaphthyl)s 4c and 4d were scarcely obtained when 3c and 3d were employed.     

Note Copolymerization of Styrene with Maleic Anhydride Initiated by L-Ascorbic Acid

It is well known that maleic anhydride (MAH) behaves as an electron acceptor and forms charge-transfer complexes with donor monomers such as styrene (ST) [1,2], divinyl ether [3], and some of other olefms [4–61. The charge-transfer polymerization of ST with MAH has been extensively studied [1,7–11]. On the other hand, L-ascorbic acid (L-Asc) in combination with a suitable oxidants proved to be an efficient redox initiator for various vinyl polymerizations. Misra et al. [12] showed that the reduction of peroxides by ascorbic acid follows a chain mechanism with ascorbate and other free radicals as intermediates. Thus, we can expect that such an electron donor might initiate the copolymerization of MAH with ST.     

Functionalization of ‘kite’ shaped styryl end-capped benzodithiophene with ketone groups: synthesis, characterization and properties

We report the synthesis of a new bridged end-capped distyryldithiophene with ketone groups on the bridge: E,E-2,7′-bis((2-phenyl)-ethenyl)-benzo[2,1-b:3,4-b′]dithiophene-4,5-dione 1. Optical and electrochemical properties of 1 in solution were investigated by UV-vis absorption and cyclic voltammetry and compared to the unsubstituted parent molecule (KDS2T). Morphology of 1-based thin films was investigated by scanning electron microscopy (SEM) and the crystalline structure characterization by X-ray diffraction (XRD). Thin films were implemented as active layers into organic thin-film transistors (OTFT) in top contact configuration to evaluate the charge transport properties.     

Selective synthesis of functionalized allylic compounds by Pd(0)-catalyzed three-component reaction of methyl propargyl carbonate with phenols and nucleophiles

A Pd(0)-catalyzed three-component reaction of methyl propargyl carbonate with phenols and nucleophiles is described. The reaction proceeded smoothly and various allylic compounds were synthesized selectively in good to excellent yields under neutral conditions. The regioselective introduction of functional groups into the allylic compounds could also be achieved. The reaction with nitrogen and carbon nucleophiles afforded mainly 2-aryloxyallylic compounds. On the other hand, aliphatic alcohols gave 2-alkoxyallylic compounds.