Statistical theory for hydrogen bonding fluid system of A a D d type (I): The geometrical phase transition

The influence of hydrogen bonds on the physical and chemical properties of hydrogen bonding fluid system of A _a D _d type is investigated from two viewpoints by the principle of statistical mechanics. In detail, we proposed two new ways that can be used to obtain the equilibrium size distribution of the hydrogen bonding clusters, and derived the analytical expression of a relationship between the hydrogen bonding free energy and hydrogen bonding degree. For the nonlinear hydrogen bonding systems, it is shown that the sol-gel phase transition can take place under proper conditions, which is further proven to be a kind of geometrical phase transition rather than a thermodynamic one. Moreover, several problems associated with the geometrical phase transition and liquid-solid phase transition in nonlinear hydrogen bonding systems are discussed.     

Comparative pharmacophore modeling of human adenosine receptor A1 and A3 antagonists

Adenosine receptors are promising therapeutic targets in drug discovery. In this study, three-dimensional pharmacophore models of human adenosine receptor A1 and A3 antagonists were developed based on 26 and 23 diverse compounds, respectively. The best A1 pharmacophore model (A 1 _Hopy1) consists of four features: one hydrogen bond donor, one hydrophobic point and two ring aromatics, while the best A 3 pharmacophore model (A3 _Hopy1) also has four features: one hydrogen bond acceptor, one hydrophobic point and two ring aromatics. The correlation coefficients were 0.840 for A 1 test set with 146 diverse compounds and 0.827 for A3 test set with 238 diverse compounds. In the simulated virtual screening experiments, high enrichment factors of 6.51 and 6.90 were obtained for A 1 _Hopy1 and A3 _Hopy1 models, respectively. Moreover, two models also showed high subtype-selectivity in the simulated virtual screening experiments. These results could be helpful for the discovery of novel potent and selective A 1 and A3 antagonists.     

Diversity of potential hydrogen bonds in cellulose I revealed by molecular dynamics simulation

We have performed molecular dynamics calculations using a revised version of the Gromos56A_carbo force field to understand the consequences of the different potential hydrogen bonding patterns on the structural stability and thermal behavior of the I_α and I_β forms of native cellulose. For each allomorph, we considered three patterns of hydrogen bonds: two patterns obtained from neutron diffraction data refinement and a regular mixture of the two. Upon annealing, the hydrogen bonding schemes of cellulose I_β, irrespective of the starting structure, re-arranged into the main hydrogen bond pattern experimentally observed (pattern A). On the other hand, the I_α structures, irrespective of the starting hydrogen bonding pattern, converged to a non-experimental structure where the adjacent chains are shifted along the chain direction by 0.12 nm in the hydrogen-bonded plane, and the hydroxymethyl group conformation alternates between gt and tg along the chain. The exotic structure in I_α might be a consequence of a deficiency in force field parameters and/or potential molecular arrangement in less crystalline cellulose.     

Statistical theory for hydrogen bonding fluid system of AaDd type (I): The geometrical phase transition

The influence of hydrogen bonds on the physical and chemical properties of hydrogen bonding fluid system of A _a D _d type is investigated from two viewpoints by the principle of statistical mechanics. In detail, we proposed two new ways that can be used to obtain the equilibrium size distribution of the hydrogen bonding clusters, and derived the analytical expression of a relationship between the hydrogen bonding free energy and hydrogen bonding degree. For the nonlinear hydrogen bonding systems, it is shown that the sol-gel phase transition can take place under proper conditions, which is further proven to be a kind of geometrical phase transition rather than a thermodynamic one. Moreover, several problems associated with the geometrical phase transition and liquid-solid phase transition in nonlinear hydrogen bonding systems are discussed.     

Halogen bonding in complexes of proteins and non-natural amino acids

In this work, we have analyzed the influence of halogen bonding to the stability of 44 complexes of proteins and non-natural amino acids. Fluorine- and chlorine-containing non-natural amino acids are more prevalent in the dataset, and an even larger number of contacts made by iodine-containing ligands are found. Only few halogen bonds with the hydroxyl oxygens and carboxylate side chains are found in the dataset. Halogen bonds with the nitrogen-containing side chains have higher occurrence than other acceptors. Backbone carbonyl oxygens and nitrogens are to a substantial extent involved in our dataset. We have observed a small percentage of interactions involving water as hydrogen bond donors. Additionally, most of the interacting residues comprising the interfaces also show a great degree of conservation. There is a clear interaction hot spot at distances of 3.5–3.7 Å and Θ₁ angles of 100–120°. There is also a cluster of contacts featuring short distances (2.6–2.9 Å) but only nearly optimal Θ₁ angles (140–160°). 51.3% of stabilizing residues are involved in building halogen bonds with the non-natural amino acids. We discovered three types of structural motifs significantly over-represented: beta-turn-ir, beta-turn-il and niche-4r. The halogen-bonding statistics of the dataset do not show any preference for α-helices (36%), β-sheets (36%), or turns/coils (28%) structures. Most of the amino acid residues that were involved in halogen bonds prefer to be in the solvent excluded environment (buried). Furthermore, we have shown that in amino acid–protein complexes halogen atoms can sometimes be involved in hydrogen bonding interactions with hydrogen bonding-donors. The results from this study might be used for the rational design of halogenated ligands as inhibitors and drugs, and in biomolecular engineering.     

Smectic A liquid crystals from dihydrazide derivatives with lateral intermolecular hydrogen bonding

Six dissymmetrical dihydrazide derivatives, N-(4-alkoxybenzoyl)-N′-(4′-nitrobenzoyl) hydrazine (Cn-NO₂) and N-(4-alkoxybenzoyl)-N′-(4′-biphenyl carbonyl) hydrazine (Cn-Ph), were synthesized and investigated by means of differential scanning calorimetry, polarized optical microscopy and wide angle X-ray diffraction. The compounds exhibit smectic A₁ phase. Based on the results of ¹H NMR and variable temperature FT-IR spectroscopy, lateral intermolecular hydrogen bonding between -CO and -N-H groups was proposed and the effect of hydrogen bonding on the phase transitions was discussed. It was concluded that the combination of lateral intermolecular hydrogen bonding and microphase segregation stabilized the smectic A phase.     

A combined systems and structural modeling approach repositions antibiotics for Mycoplasma genitalium

Bacteria are increasingly resistant to existing antibiotics, which target a narrow range of pathways. New methods are needed to identify targets, including repositioning targets among distantly related species. We developed a novel combination of systems and structural modeling and bioinformatics to reposition known antibiotics and targets to new species. We applied this approach to Mycoplasma genitalium, a common cause of urethritis. First, we used quantitative metabolic modeling to identify enzymes whose expression affects the cellular growth rate. Second, we searched the literature for inhibitors of homologs of the most fragile enzymes. Next, we used sequence alignment to assess that the binding site is shared by M. genitalium, but not by humans. Lastly, we used molecular docking to verify that the reported inhibitors preferentially interact with M. genitalium proteins over their human homologs. Thymidylate kinase was the top predicted target and piperidinylthymines were the top compounds. Further work is needed to experimentally validate piperidinylthymines. In summary, combined systems and structural modeling is a powerful tool for drug repositioning.     

Cationic Exciplexes: Role of Hydrogen Bonding in Deactivation and Electronic Coupling

Emissive properties for the cationic exciplex (A⁺*/D→A^.D^.+) of an isoquinolinium cation tethered to a substituted arene ( 1⁺ ) are strongly affected by hydrogen bonding solvents. At equal dielectric constant (ϵ), the ground-to-excited state energy gaps (ΔG) and solvent reorganization energies (λ_s) decrease from nitriles to aliphatic alcohols. The corresponding decrease from aliphatic alcohols to high hydrogen bond acidity solvents is ∼3 times larger. The exciplex decay (k_Ex), largely determined by unfolding of the exciplex to a stretched conformer, changes in a complex way depending on the strength of the hydrogen bond ability of these solvents. In contrast, the electronic couplings between the exciplex ground, excited, and charge transfer states do not show a solvent functionality dependence.     

Synthesis and liquid crystal properties of a novel family of oligothiophene derivatives

In order to develop novel oligothiophene-based liquid crystals capable of hydrogen bonding, new terthiophene derivatives containing an alkylamide group, N,N′-dialkyl-5,5″-dichloro-2,2′:5′,2″-terthiophene-4,4″-dicarboxamide (DNC_nDCl3T, n=8, 18), N,N′-dialkyl-5,5″-dibromo-2,2′:5′,2″-terthiophene-4,4″-dicarboxamide (DNC_nDBr3T, n=5, 8, 16, 18), or N,N′-dialkyl-5,5″-diiodo-2,2′:5′,2″-terthiophene-4,4″-dica-rboxamide (DNC_nDI3T, n=8, 18), were designed and synthesized, and their thermal behaviour was examined. It was found that DNC₁₈DCl3T, DNC₁₈DI3T and DNC_nDBr3T (n=8, 16, 18) form a smectic A phase and that the alkyl chain length greatly affects liquid crystal phase formation. The absence of liquid crystallinity in the corresponding ester derivatives suggests that intermolecular hydrogen bonding also plays a role in the formation of a liquid crystal phases in the DNC_nDBr3T system.     

The Lysozyme Inhibitor Thionine Acetate Is Also an Inhibitor of the Soluble Lytic Transglycosylase Slt35 from Escherichia coli

Lytic transglycosylases such as Slt35 from E. coli are enzymes involved in bacterial cell wall remodelling and recycling, which represent potential targets for novel antibacterial agents. Here, we investigated a series of known glycosidase inhibitors for their ability to inhibit Slt35. While glycosidase inhibitors such as 1-deoxynojirimycin, castanospermine, thiamet G and miglitol had no effect, the phenothiazinium dye thionine acetate was found to be a weak inhibitor. IC₅₀ values and binding constants for thionine acetate were similar for Slt35 and the hen egg white lysozyme. Molecular docking simulations suggest that thionine binds to the active site of both Slt35 and lysozyme, although it does not make direct interactions with the side-chain of the catalytic Asp and Glu residues as might be expected based on other inhibitors. Thionine acetate also increased the potency of the beta-lactam antibiotic ampicillin against a laboratory strain of E. coli.     

Synthesis of branched tri- to pentasaccharides representative of fragments of Shigella flexneri serotypes 3a and/or X O-antigens

Fragments of the {2)-[α-d-Glcp-(1→3)]-α-l-Rhap-(1→2)-α-l-Rhap-(1→3)-[Ac→2]-α-l-Rhap-(1→3)-β-d-GlcpNAc-(1→}_n ((E)AB_AcCD)_n polymer were synthesized. D(E)A, CD(E)A, _AcCD(E)A were obtained according to a linear strategy, whereas BCD(E)A and B_AcCD(E)A were derived from the condensation of appropriate BC and D(E)A building blocks. Oligosaccharides were synthesized as their propyl glycoside, relying on (i) the efficient trichloroacetimidate chemistry, (ii) a common EA allyl glycoside, and (iii) a 2-trichloroacetamido-d-glucopyranose precursor to residue D. Final Pd/C-mediated deprotection, run under a high pressure of hydrogen, ensured O-acetyl stability. All targets are parts of the O-antigen of Shigella flexneri 3a, a prevalent serotype. Non-O-acetylated oligosaccharides are shared by the S. flexneri serotype X O-antigen.     

Crystal and molecular structure of 5-trifluorothymine, a metabolite from human urine: Role of fluorine in stacking and hydrogen bonded interactions

The crystal structure of the metabolite from urine, 5-trifluorothymine [5F₃T] has been determined by single crystal X-ray diffractometric methods. Crystals of 5F₃T are monoclinic, space group P2₁/c with cell dimensions a = 6.7468(2), b = 15.0740(6), c = 13.4405(6), β = 90.412(2), V = 1366.88(8), Z = 8 (two molecules per asymmetric unit). Crystal structure of 5F₃T was determined with 3039 independent data and refined by full-matrix least squares methods to a final reliability factor of 0.047. Molecules of 5F₃T are connected by dimeric type of NH?O hydrogen bonding linking molecules related by a center of inversion into an extensive layer of dimeric molecules. These layers are stacked on top of each other at a stacking distance of 3.280 Å with a head-to-head stacking of the fluorine atoms on top of each other with no hydrogen bonding involving the fluorine atoms.     

Aromatic Rings as Molecular Determinants for the Molecular Recognition of Protein Kinase Inhibitors

Protein kinases are key enzymes in many signal transduction pathways, and play a crucial role in cellular proliferation, differentiation, and various cell regulatory processes. However, aberrant function of kinases has been associated with cancers and many other diseases. Consequently, competitive inhibition of the ATP binding site of protein kinases has emerged as an effective means of curing these diseases. Over the past three decades, thousands of protein kinase inhibitors (PKIs) with varying molecular frames have been developed. Large-scale data mining of the Protein Data Bank resulted in a database of 2139 non-redundant high-resolution X-ray crystal structures of PKIs bound to protein kinases. This provided us with a unique opportunity to study molecular determinants for the molecular recognition of PKIs. A chemoinformatic analysis of 2139 PKIs resulted in findings that PKIs are “flat” molecules with high aromatic ring counts and low fractions of sp³ carbon. All but one PKI possessed one or more aromatic rings. More importantly, it was found that the average weighted hydrogen bond count is inversely proportional to the number of aromatic rings. Based on this linear relationship, we put forward the exchange rule of hydrogen bonding interactions and non-bonded π-interactions. Specifically, a loss of binding affinity caused by a decrease in hydrogen bonding interactions is compensated by a gain in binding affinity acquired by an increase in aromatic ring-originated non-bonded interactions (i.e., π–π stacking interactions, CH–π interactions, cation–π interactions, etc.), and vice versa. The very existence of this inverse relationship strongly suggests that both hydrogen bonding and aromatic ring-originated non-bonded interactions are responsible for the molecular recognition of PKIs. As an illustration, two representative PKI–kinase complexes were employed to examine the relative importance of different modes of non-bonded interactions for the molecular recognition of PKIs. For this purpose, two FDA-approved PKI drugs, ibrutinib and lenvatinib, were chosen. The binding pockets of both PKIs were thoroughly examined to identify all non-bonded intermolecular interactions. Subsequently, the strengths of interaction energies between ibrutinib and its interacting residues in tyrosine kinase BTK were quantified by means of the double hybrid DFT method B2PLYP. The resulting energetics for the binding of ibrutinib in tyrosine kinase BTK showed that CH–π interactions and π–π stacking interactions between aromatic rings of the drug and hydrophobic residues in its binding pocket dominate the binding interactions. Thus, this work establishes that, in addition to hydrogen bonding, aromatic rings function as important molecular determinants for the molecular recognition of PKIs. In conclusion, our findings support the following pharmacophore model for ATP-competitive kinase inhibitors: a small molecule features a scaffold of one or more aromatic rings which is linked with one or more hydrophilic functional groups. The former has the structural role of acting as a scaffold and the functional role of participating in aromatic ring-originated non-bonded interactions with multiple hydrophobic regions in the ATP binding pocket of kinases. The latter ensure water solubility and form hydrogen bonds with the hinge region and other hydrophilic residues of the ATP binding pocket.     

FTIR study on molecular structure of poly(N-isopropylacrylamide) in mixed solvent of methanol and water

The intrachain and interchain hydrogen bonding of poly(N-isopropylacrylamide) (PNIPA) and intermolecular hydrogen bonding between PNIPA chains and the solvent molecules in the mixed solvent of methanol and water have been quantitatively investigated by using Fourier transform infrared (FTIR) spectroscopy at 25 °C. In this spectroscopic system with curve fitting program, we found that in the C-H stretching region, both the N-isopropyl group and the backbone underwent conformational change upon the solvent composition. An analysis of the amide I band suggested that the amide groups of PNIPA were mainly involved in intermolecular hydrogen bonding with water molecules, and the polymer chains were flexible and disordered in the mixed solvent when the methanol volume fraction (χ_v) was lower than 15%. While χ_v was in the range of 15-65%, about 30% of these intermolecular hydrogen bonding between the polymer and water were replaced by intrachain and interchain hydrogen bonding, consequently, PNIPA shrinked as aggregates. If χ_v was above 65%, the interchain hydrogen bonding became predominant due to the solubility characteristics of amphiphilic methanol, and the PNIPA system was homogeneous solution again. We believe that the reentrant transition is related to the weaker interaction between PNIPA molecules and methanol-water complexes, (H₂O)_m(CH₃OH)_n (m/n = 5/1, 5/2, 5/3, 5/4, 5/5) as compared to that between PNIPA and free water or free methanol.     

Drug Repurposing for Influenza Virus Polymerase Acidic (PA) Endonuclease Inhibitor

Drug repurposing can quickly and effectively identify novel drug repurposing opportunities. The PA endonuclease catalytic site has recently become regarded as an attractive target for the screening of anti-influenza drugs. PA N-terminal (PA_N) inhibitor can inhibit the entire PA endonuclease activity. In this study, we screened the effectivity of PA_N inhibitors from the FDA database through in silico methods and in vitro experiments. PA_N and mutant PA_N-I38T were chosen as virtual screening targets for overcoming drug resistance. Gel-based PA endonuclease analysis determined that the drug lifitegrast can effectively inhibit PA_N and PA_N-I38T, when the IC₅₀ is 32.82 ± 1.34 μM and 26.81 ± 1.2 μM, respectively. Molecular docking calculation showed that lifitegrast interacted with the residues around PA or PA-I38 T’s active site, occupying the catalytic site pocket. Both PA_N/PA_N-I38T and lifitegrast can acquire good equilibrium in 100 ns molecular dynamic simulation. Because of these properties, lifitegrast, which can effectively inhibit PA endonuclease activity, was screened through in silico and in vitro research. This new research will be of significance in developing more effective and selective drugs for anti-influenza therapy.     

A system-independent correlation between the enthalpy and the entropy of dilution for polymer solutions

The second osmotic virial coefficient (A₂) and its entropic and enthalpic parts (A_2,s and A_2,H) have been determined, by means of light-scattering measurements, for solutions of polystyrene, polymethylmethacrylate and cellulose nitrate of different molecular weights in 19 solvents. A distinct qualitative correlation exists between A₂ and A_2,H and between A_2,s and A_2,H. The elimination of the “geometric” parameters of the polymer, by dividing these coefficients by suitably chosen reduction parameters, shows that the reduced coefficients obtained A₂⁰ and A_2,s⁰ are predominantly functions of the reduced enthalpy coefficient A_2,H⁰.     

Synthesis and structural characterization of a novel organic-inorganic supermoleculer of [FeII(Phen)3]L2 · 2H2O complex

A new organic-inorganic complex [Fe^II(Phen)₃]L₂ · 2H₂O (Phen = 1,10-phenanthroline, L = 2-mercaptonicotinic acid) was synthesized and characterized. The crystal structure of the complex was determined by single-crystal X-ray diffraction, crystallizing in orthorhombic crystal system, space group Pba2 with the unit cell parameters a = 13.4711(11), b = 17.0021(14), c = 11.7026(9) Å, and Z = 2. The Fe(II) atom was six-coordinated with N(1), N(1A), N(2), N(2A), N(3), and N(3A) from three Phen ligands and formed a slightly distorted octahedral geometry. The base units form a one-dimensional chain via π-π-stacking interaction between 2-mercaptonicotinic acid fragments. A new 3D layered compound was obtained through hydrogen bonding.     

First-principles calculations of the stability and hydrogen storage behavior of C14 Laves phase compound TiCrMn

The structural, elastic properties, electronic structure and hydrogen storage behavior of TiCrMn with a hexagonal C14 structure were investigated by the first-principles calculations within the frame work of DFT. The calculated lattice constants were consistent with the experimental values, and obtained cohesive energy and formation enthalpy showed TiCrMn is of the structural stability. These results also indicated that Mn atoms would optionally substitute on the Cr sites of TiCr₂ phase to form the ternary intermetallic TiCrMn. The five independent elastic constants as well as polycrystalline elastic parameters (bulk modulus B, shear modulus G, Young's modulus E, Poisson's ratio ν and anisotropy value A) were calculated, and then the ductility and elastic anisotropy of TiCrMn were discussed in details. Furthermore, the electronic DOS and charge density distribution of TiCrMn were also calculated, which revealed the underlying mechanism of structural stability and chemical bonding. Finally, the binding energy of hydrogen in hydride TiCrMn(H₃) was investigated, confirming the better hydrogen storage behavior of C14 Laves phase TiCrMn.     

Phytochemistry,antioxidant and antibacterial activities of two Moroccan Teucrium polium L. subspecies: Preventive approach against nosocomial infections

The aim of the present study was to determine the chemical composition and antioxidant activity of essential oils (EOs) from two Teucrium polium subspecies, to evaluate, also their antibacterial activities, against some nosocomial-bacteria. The phytochemical screening of essential oils was analyzed using gas chromatography-flame ionization detector (GC-FID) and gas chromatography-mass spectrometry analysis (GC-MS). The antibacterial activities were assessed by disc diffusion method and minimal inhibitory concentration (MIC), against Gram-negative bacteria (Escherichia coli, Klebsiella pneumoniae, Pseudomonas aeruginosa, Citrobacter koseri and Acinetobacter baumannii) and Gram-positive bacteria Staphylococcus aureus. The antioxidant potential was evaluated in vitro by three assays, namely free radical scavenging activity against 1,1-diphenyl-2-picrylhydrzyl (DPPH), ferric reducing activity power (FRAP) and total antioxidant capacity. Twenty-six components were identified in the EO of Teucrium polium subsp. aurum representing. Its major component was Caryophyllene (19.13%) followed by γ-Muurolene (13.02%), τ-cadinol, (11.01%), α-Gurjunene (9.2%), Rosifoliol (8.79%), 3-Carene (7.04%). However, twenty two components were identified in the EO of T. polium subsp. polium. Its major components are 3-carene (16.49%), γ-Muurolene (14.03%), α-pinene (9.94%), α-phellandrene (6.93%) and Caryophyllene (7.51%). The antibacterial activity of both essential oils showed a higher activity against tested nosocomial bacteria especially against S. aureus and A. baumannii. The EO of T. polium subsp. aureum showed better antioxidant activity as measured by DPPH and FRAP assays with IC₅₀ values of 3.7 ± 0.2 mg/ml and 2.31 ± 0.11 mg/ml, respectively. The total antioxidant capacity assay showed that T. polium subsp. aureum had a significant activity with value to 3308.27 mg equivalent to ascorbic acid/g of EO. The Moroccan T. polium essential oils could be exploited as an antimicrobial agent for the treatment of several infectious diseases caused by bacteria, especially, those who have developed resistance to conventional antibiotics.     

Rate and thermodynamic studies of the interaction between water and iso-butyl cellosolve by ultrasonic methods

Ultrasonic absorption and velocity measurements in aqueous solution of iso-butyl cellosolve (ethylene glycol iso-butyl ether) as a function of the concentration are reported. The two relaxational absorptions have been attributed to the perturbation of the equilibria expressed by AB?A+B and Aα(1/n)A_n where A is the solute, B is the solvent, AB is the complex and A _n is the solute aggregate. The rate constants for each step have been determined. From the concentration dependence of the maximum excess absorption per wave length, the enthalpy change and the volume change for the reaction between the solute and the solvent have been determined for aqueous solutions of butyl cellosolve (ethylene glycol n-butyl ether), iso-butyl cellosolve and propyl cellosolve (ethylene glycol n-propyl ether). The results are consistent with a hydrogen bonding reaction. The effect of the ethers on water structure are considered and it is clear that the fraction of water molecules which can hydrogen bond to the solute decreases with the increasing hydrophobicity of the solute.