Binding affinity of substituted ureido‐benzenesulfonamide ligands to the carbonic anhydrase receptor: A theoretical study of enzyme inhibition

The binding properties of a series of benzenesulfonamide inhibitors (4‐substituted‐ureido‐benzenesulfonamides, UBSAs) of human carbonic anhydrase II (hCA II) enzyme with active site residues have been studied using a hybrid quantum mechanical/molecular mechanical (QM/MM) model. To account for the important docking interactions between the UBSAs ligand and hCA II enzyme, a molecular docking program AutoDock Vina is used. The molecular docking results obtained by AutoDock Vina revealed that the docked conformer has root mean square deviation value less than 1.50 Å compared to X‐ray crystal structures. The inhibitory activity of UBSA ligands against hCA II is found to be in good agreement with the experimental results. The thermodynamic parameters for inhibitor binding show that hydrogen bonding, hydrophilic, and hydrophobic interactions play a major role in explaining the diverse inhibitory range of these derivatives. Additionally, natural bond orbital analysis is performed to characterize the ligand–metal charge transfer stability. The insights gained from this study have great potential to design new hCA‐II inhibitor, 4‐[3‐(1‐p‐Tolyl‐4‐trifluoromethyl‐1H‐pyrazol‐3‐yl)‐ureido]‐benzenesulfonamide, which belongs to the family of UBSA inhibitors and shows similar type of inhibitor potency with hCA II. This work also reveals that a QM/MM model and molecular docking method are computationally feasible and accurate for studying substrate–protein inhibition. © 2013 Wiley Periodicals, Inc.     

Non-covalent synthesis of ionic and molecular complexes of benzoic acid and substituted 2-aminopyrimidines by varying aryl/alkyl substituents and their supramolecular chemistry

The non-covalent synthesis of ionic and molecular complexes of substituted 2-aminopyrimidines with benzoic acid in crystalline solid phase is reported. The nature of supramolecular architecture varied with the substituents in the 2-aminopyrimidine ring. Two complexes have been synthesised from two differently substituted 2-aminopyrimidines and benzoic acid. In one case, proton transfer takes place and an ionic organic salt is formed, whereas in the other, there is no proton transfer and a hydrogen-bonded molecular complex is formed.     

Cobamide Structure Depends on Both Lower Ligand Availability and CobT Substrate Specificity

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Interfacial rheology of mixed layers of food proteins and surfactants

Mixed protein–surfactant adsorption layers at liquid interfaces are described including the thermodynamic basis, the adsorption kinetics and the shear and dilational interfacial rheology. It is shown that due to the protrusion of hydrophobic protein parts into the oil phase the adsorption layers at the water–hexane interface are stronger anchored as compared to the water-air surface. Based on the different adsorption protocols, a sequential and a simultaneous scheme, the peculiarities of complexes between proteins and added surfactants are shown when formed in the solution bulk or at a liquid interface. The picture drawn from adsorption studies is supported by the findings of interfacial rheology.     

Dispersion corrected double high-hybrid and gradient-corrected density functional theory study of light cation–dihydrogen (M+–H2, where M = Li, Na, B and Al) van der Waals complexes

Structure, frequencies, H–H stretching frequency shifts, interaction energy, depth of the potential well and dissociation energy of the light cation–dihydrogen (M⁺–H₂, where M = Li, Na, B, and Al) van der Waals complexes have been studied in detail using dispersion corrected double-hybrid and gradient-corrected density functional methods in conjunction with correlation consistent valence triple-ζ basis set. Equilibrium bond distance and dissociation energy agree very well with the experimental and theoretical values wherever available. The dissociation energies of Li⁺–H₂, B⁺–H₂, Na⁺–H₂, and Al⁺–H₂ van der Waals complexes calculated from the potential energy curves at mPW2PLYP-D/cc-pVTZ level are 4.83, 3.68, 2.42, and 1.25 kcal/mol, respectively, at a distances of 1.95, 2.25, 2.40, and 2.95 Å. Among all these complexes, Al⁺–H₂ complex is comparatively less stable, as their dissociation energy as well as depth of the potential well are smaller compared to others complexes. The symmetry-adapted perturbation theory (SAPT) has been applied to quantify the nature of interactions. The SAPT results show that the contribution of dispersion and induction are significant, although electrostatic dominates.     

Supramolecular Host‐Inhibited Excited‐State Proton Transfer and Fluorescence Switching of the Anti‐Cancer Drug,Topotecan

The effect of cucurbit[7]uril (CB[7]) nano‐caging on the photophysical properties, particularly excited‐state proton transfer (ESPT) reaction, of an eminent anti‐cancer drug, topotecan (TPT), is demonstrated through steady‐state and time‐resolved fluorescence measurements. TPT in water (pH 6) exists exclusively as the cationic form (C) in the ground state. However, the drug emission mainly comes from the excited‐state zwitterionic form (Z*) of TPT, and is attributed to water‐assisted ESPT between the 10‐hydroxyl group and water, which leads to the transformation of C* to Z* of TPT. In the presence of CB[7], it is found that selective encapsulation of the C form of TPT results in the formation of a 1:1 inclusion complex (CB[7]:TPT), and the ESPT process is inhibited by this encapsulation process. As a result, C* becomes the dominant emitting species in the presence of CB[7] rather than Z*, and fluorescence switching takes place from green to blue. Time‐resolved studies also support the existence of CB[7]‐encapsulated cationic species as the major emitting species in the presence of the macrocyclic host. Semi‐empirical quantum chemical calculations are employed to gain insight into the molecular picture of orientation of TPT in the inclusion complex. It is clearly seen from the optimised structure of 1:1 CB[7]:TPT inclusion complex that both 10‐hydroxyl and 9‐dimethylaminomethylene groups of TPT lie partly inside the cavity, and thereby inhibit the excited‐state transformation of C* to Z* by the ESPT process. Finally, controlled release of the drug is achieved by means of fluorescence switching by introducing NaCl, which is rich in cells, as an external stimulus.     

Synergistic Role of Bacterial Urease and Carbonic Anhydrase in Carbonate Mineralization

The investigation on the synergistic role of urease (UA) and carbonic anhydrase (CA) in biomineralization of calcium carbonate in Bacillus megaterium suggested that the precipitation of CaCO₃ is significantly faster in bacterial culture than in crude enzyme solutions. Calcite precipitation is significantly reduced when both the enzymes are inhibited in comparison with those of the individual enzyme inhibitions indicating that both UA and CA are crucial for efficient mineralization. Carbonic anhydrase plays a role in hydrating carbon dioxide to bicarbonate, while UA aids in maintaining the alkaline pH that promotes calcification process.     

A missing enzyme in thiamin thiazole biosynthesis: identification of TenI as a thiazole tautomerase

In many bacteria tenI is found clustered with genes involved in thiamin thiazole biosynthesis. However, while TenI shows high sequence similarity with thiamin phosphate synthase, the purified protein has no thiamin phosphate synthase activity, and the role of this enzyme in thiamin biosynthesis remains unknown. In this contribution, we identify the function of TenI as a thiazole tautomerase, describe the structure of the enzyme complexed with its reaction product, identify the substrates phosphate and histidine 122 as the acid/base residues involved in catalysis, and propose a mechanism for the reaction. The identification of the function of TenI completes the identification of all of the enzymes needed for thiamin biosynthesis by the major bacterial pathway.