Insights into Modeling Approaches in Chemistry: Assessing Ligand-Protein Binding Thermodynamics Based on Rigid-Flexible Model Molecules

In the field of chemistry, model compounds find extensive use for investigating complex objects. One prime example of such object is the protein-ligand supramolecular interaction. Prediction the enthalpic and entropic contribution to the free energy associated with this process, as well as the structural and dynamic characteristics of protein-ligand complexes poses considerable challenges. This review exemplifies modeling approaches used to study protein-ligand binding (PLB) thermodynamics by employing pairs of conformationally constrained/flexible model molecules. Strategically designing the model molecules can reduce the number of variables that influence thermodynamic parameters. This enables scientists to gain deeper insights into the enthalpy and entropy of PLB, which is relevant for medicinal chemistry and drug design. The model studies reviewed here demonstrate that rigidifying ligands may induce compensating changes in the enthalpy and entropy of binding. Some “rules of thumb” have started to emerge on how to minimize entropy-enthalpy compensation and design efficient rigidified or flexible ligands.     

Chemical interaction in the B-BN system at high pressures and temperatures.: Synthesis of novel boron subnitrides

Chemical interaction and phase transformations in the B-BN system have been in situ studied by X-ray diffraction with synchrotron radiation at pressures up to 5.3 GPa and temperatures up to 2800 K using multianvil press. New rhombohedral boron subnitride B₁₃N₂ has been synthesized by crystallization from the B-BN melt at 5 GPa. The structure of B₁₃N₂ belongs to the R-3m space group (a=5.4455(2) Å, c=12.2649(9) Å) and represents a new structural type. The subnitride is an individual compound and not a solid solution, in contrast to boron carbide. Besides, the formation of two other boron-rich B-N phases denoted as “B₆N” and “B₅₀N₂” has been observed. Their structures seem to be much more sophisticated and have not been even resolved to present time.     

Synthesis,Anticancer, and QSAR Studies of 2‐Alkyl(aryl,hetaryl)quinazolin‐4(3H)‐thione's and [1,2,4]Triazolo[1,5‐c]quinazoline‐2‐thione's Thioderivatives

Considering the frightening high level of mortality from cancer, studies of anticancer agents are vital nowadays. The 24 thioderivatives of 2‐alkyl(aryl)‐quinazolin‐4(3H)‐thiones and 20 thioderivatives of [1,2,4]triazolo[1,5‐c]quinazoline‐2‐thiones were synthesized and evaluated for preliminary in vitro anticancer activity with subsequent in silico QSAR analysis. The substance 18 had the best results inhibiting growth of eight cancer cell lines: CCRF‐CEM of leukemia; SF‐539, SNB‐75, and U251 of CNS cancer; 786, RXF393, and UO‐31 of renal cancer; and MDA‐MB‐231/ATCC of breast cancer (?31.50 – 47.41% of cell growth) with low procancer effect. Calculated QSAR‐models for CCRF‐CEM of leukemia, T‐47D and HS 578T of breast cancer, and mean cell growth demonstrated good rate of anticancer activity prediction (r² = 0.7 – 0.8,  = 0.5 – 0.7).     

All-fiber Kerr cell

An all-fiber nanosecond Kerr light gate is described that was constructed using microstructured fibers. The switching voltage for a 20?cm long device is as low as Vπ～85 V at a 1.06?μm wavelength. The device is fully spliced. The active element is a three-hole fiber provided with internal electrodes in the side-holes and a liquid core of nitrobenzene, which is fully enclosed. This work allows the exploiting of electrically driven liquid-core fibers and demonstrated the removal of the major limitations of Kerr cells in the past, allowing for integration, safe use, and relatively low switching voltage.     

Quantification of local hydration at the surface of biomolecules using dual-fluorescence labels

By using four labels of the 3-hydroxyflavone family displaying selective sensitivity to hydrogen bond (HB) donors and poor response to other polar molecules, we developed an approach for measuring local water concentration [H(2)O](L) (or partial volume of water: W(A) = [H(2)O](L)/55.6) in the label surrounding both in solvent mixtures and in biomolecules by the intensity ratio of two emissive forms of the label, N*/T*. Using a series of binary water/solvent mixtures with limited preferential solvation effects, a linear dependence of log(N*/T*) on the local concentration of HB donor was obtained and then used as a calibration curve for estimating the W(A) values in the surroundings of the probes conjugated to biomolecules. By this approach, we estimated the hydration of the labels in different peptides and their complexes with DNAs. We found that W(A) values for the label at the peptide N-terminus are lower (0.63-0.91) than for free labels and depend strongly on the nature of the N-terminal amino acid. When complexed with different DNAs, the estimated hydration of the labels conjugated to the labeled peptides was much lower (W(A) = 0-0.47) and depended on the DNA nature and linker-label structure. Thus, the elaborated method allows a site-specific evaluation of hydration at the surface of a biomolecule through the determination of the partial volume of water. We believe the developed procedure can be successfully applied for monitoring hydration at the surface of any biomolecule or nanostructure.     

Recyclizations of 3-formylchromones with binucleophiles

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Synthesis of a novel Boc-protected cyclopropane-modified proline analogue

The synthesis of the Boc derivative of a novel member of the cyclopropane-modified proline library, Boc-protected 5-azaspiro[2.4]heptane-6-carboxylic acid, is reported. The synthesis was performed in six steps starting from (2S,4R)-4-hydroxyproline using a modified Simmons-Smith reaction as the key step. The reaction conditions for all the steps were carefully selected to avoid racemization at the chiral centers in the intermediates and the final product.     

1-Alkyl-5-((di)alkylamino) tetrazoles: building blocks for peptide surrogates

An approach to the synthesis of 1-alkyl-5-((di)alkylamino)tetrazoles by nucleophilic substitution in 1-alkyl-5-sulfonyltetrazoles with anions generated from the primary or secondary amines was developed. Tolerance of the method to the presence of some functional groups (i.e., protected amine) in both components of the reaction was demonstrated. Obtained tetrazoles are promising building blocks for the design of peptide surrogates, in particular, for replacement approaches of alkyl urea derivatives.     

Temperature-Dependent Photoluminescence of Silver-Indium-Sulfide Nanocrystals in Aqueous Colloidal Solutions

The temperature dependence of the photoluminescence (PL) intensity of colloidal semiconductor nanocrystals (NCs) makes them an appealing option in bio-sensing applications. Here, we probed the temperature-dependent PL behavior of aqueous glutathione (GSH)-capped Ag−In−S (AIS) NCs and their core/shell AIS/ZnS heterostructures. We show that both core and core-shell materials reveal strong PL quenching upon heating from 10 to 80 °C, which is completely reversible upon cooling. The PL quenching is assigned to the thermally activated dissociation of complexes formed by ligands with the metal cations on the NC surface and the introduction of water into the NC coordination sphere. This unique mechanism of the thermal PL quenching results in a much higher temperature sensitivity of the aqueous colloidal AIS (AIS/ZnS) NCs as compared with previously reported analogs capped by covalently bound ligands. Our results are expected to stimulate further studies on aqueous ternary NCs as colloidal luminescent nano-thermometers applicable for ratiometric temperature sensing.