Donor Capacity Research Articles

Computational models on quantitative prediction of bioactivity of HIV-1 integrase 3’ processing inhibitors

In this study, four computational quantitative structure–activity relationship (QSAR) models were built to predict the bioactivity of 3’ processing (3’P) inhibitors of HIV-1 integrase. Some 453 inhibitors whose bioactivity values were detected by the radiolabelling method were collected. The molecular structures were represented with MOE descriptors. In total, 21 descriptors were selected for modelling. All inhibitors were divided into a training set and a test set with two methods: (1) by a Kohonen’s self-organizing map (SOM); (2) by a random selection. For every training set and test set, a multilinear regression (MLR) analysis and a support vector machine (SVM) were used to establish models, respectively. For the training/test set divided by SOM, the correlation coefficients (r) were over 0.84, and for the training/test set split randomly, the r values were over 0.86. Some molecular properties such as hydrogen bond donor capacity, atomic partial charge properties, molecular refractivity, the number of aromatic bonds and molecular surface area, volume and shape properties played important roles for inhibiting 3’ processing step of HIV-1 integrase.

Analysis of organophosphate–Zn metalloporphyrin interactions via UV–vis spectroscopy and molecular modeling

UV–vis absorption spectra of zinc tetraphenylporphine (ZnTPP) on interaction with six organophosphorus (OP) compounds in cyclohexane were compared using ab initio methods and the molecular and solvation ligand descriptors π*, Vx, and σ. OPs with polarizable hydrocarbon substituents in the homologous series tri-ethyl, -pentyl, -octyl, and -phenyl phosphates and the toxicologically relevant methyl paraoxon (1a–e) each gave a red shift in the Soret band (λsor) of ZnTPP in the range of 8–10nm. Sensitivity as ΔAsor-b/Δug OP for the spectral band of the ligand bound ZnTPP (λsor-b) decreased with increasing extent of alkyl and aromatic substitution. Calculated and combined energies for OP and ZnTPP examined as a function of distance (Å) between ligand and porphyrin center suggest increased steric crowding with increasing Vx, and aromatic content of the OP. Spectrally fitted K1:1 and ΔAsor-b/ug OP each vary exponentially with Vx/σ. Lack of a red shift in λsor-b where ZnTPP was titrated with the toxic diethyl chlorophosphate (1g) is consistent with a model in which the magnitude of ΔEsor is proportional to the donor capacity of the phosphoryl-O ligand.

Modeling biophysical and biological properties from the characteristics of the molecular electron density, electron localization and delocalization matrices, and the electrostatic potential.

The electron density and the electrostatic potential are fundamentally related to the molecular hamiltonian, and hence are the ultimate source of all properties in the ground- and excited-states. The advantages of using molecular descriptors derived from these fundamental scalar fields, both accessible from theory and from experiment, in the formulation of quantitative structure-to-activity and structure-to-property relationships, collectively abbreviated as QSAR, are discussed. A few such descriptors encode for a wide variety of properties including, for example, electronic transition energies, pKa's, rates of ester hydrolysis, NMR chemical shifts, DNA dimers binding energies, π-stacking energies, toxicological indices, cytotoxicities, hepatotoxicities, carcinogenicities, partial molar volumes, partition coefficients (log P), hydrogen bond donor capacities, enzyme–substrate complementarities, bioisosterism, and regularities in the genetic code. Electronic fingerprinting from the topological analysis of the electron density is shown to be comparable and possibly superior to Hammett constants and can be used in conjunction with traditional bulk and liposolubility descriptors to accurately predict biological activities. A new class of descriptors obtained from the quantum theory of atoms in molecules' (QTAIM) localization and delocalization indices and bond properties, cast in matrix format, is shown to quantify transferability and molecular similarity meaningfully. Properties such as “interacting quantum atoms (IQA)” energies which are expressible into an interaction matrix of two body terms (and diagonal one body “self” terms, as IQA energies) can be used in the same manner. The proposed QSAR-type studies based on similarity distances derived from such matrix representatives of molecular structure necessitate extensive investigation before their utility is unequivocally established. © 2014 The Author and the Journal of Computational Chemistry Published by Wiley Periodicals, Inc.

Rational Design of a New Trypanosoma rangeli Trans-Sialidase for Efficient Sialylation of Glycans

This paper reports rational engineering of Trypanosoma rangeli sialidase to develop an effective enzyme for a potentially important type of reactivity: production of sialylated prebiotic glycans. The Trypanosoma cruzi trans-sialidase and the homologous T. rangeli sialidase has previously been used to investigate the structural requirements for trans-sialidase activity. We observed that the T. cruzi trans-sialidase has a seven-amino-acid motif (197–203) at the border of the substrate binding cleft. The motif differs substantially in chemical properties and substitution probability from the homologous sialidase, and we hypothesised that this motif is important for trans-sialidase activity. The 197–203 motif is strongly positively charged with a marked change in hydrogen bond donor capacity as compared to the sialidase. To investigate the role of this motif, we expressed and characterised a T. rangeli sialidase mutant, Tr13. Conditions for efficient trans-sialylation were determined, and Tr13's acceptor specificity demonstrated promiscuity with respect to the acceptor molecule enabling sialylation of glycans containing terminal galactose and glucose and even monomers of glucose and fucose. Sialic acid is important in association with human milk oligosaccharides, and Tr13 was shown to sialylate a number of established and potential prebiotics. Initial evaluation of prebiotic potential using pure cultures demonstrated, albeit not selectively, growth of Bifidobacteria. Since the 197–203 motif stands out in the native trans-sialidase, is markedly different from the wild-type sialidase compared to previous mutants, and is shown here to confer efficient and broad trans-sialidase activity, we suggest that this motif can serve as a framework for future optimization of trans-sialylation towards prebiotic production.

Effective Use of Monitoring and Evaluation Systems in Managing HIV/AIDS Related Projects: A Case Study of Local NGOS in Kenya

Close monitoring and evaluation during implementation leads to projects success. This study sought to determine how effectively the HIV/AIDS projects implemented by NGOs in Kenya are monitored and evaluated as laid down by the current National HIV/AIDS Monitoring and Evaluation Framework found in the Kenya National AIDS Strategic Plan 2009/10-2012/13 (KNASP III). The research considered several factors that affect the effective use of Monitoring and Evaluation by project managers in NGOs with HIV/AIDS projects in Kenya. These include lack of commitment by the project managers, incompetency on the use of the Monitoring and Evaluation systems by project managers, stringent donor requirements and capacity constraints of the NGOs. The data collected was analyzed using both quantitative and qualitative techniques. Measures of central tendency that is the mean, mode, and median were computed and interpreted. The data is presented using frequency distribution tables, pie charts and bar graphs. Relationship between various variables is established using simple correlation and regression. The researcher has used the software of Statistical Package for Social Sciences (SPSS) and the Ms-Excel. The data is also given in narrative form for explanation of situations. High ethical standards were maintained by the researcher. The study is significant in that has established the status of effective use of Monitoring and Evaluation in NGOs dealing with the HIV/AIDS pandemic in Kenya. This will contribute towards filling the present knowledge gap. The study will also form a basis on which other studies can be carried out.

Reactions of p‐Substituted Phenols with Nitrous Acid in Aqueous Solution

ABSTRACTThe reaction of phenols with nitrite (nitrous acid HONO, or its conjugated base, NO2−) is of importance in stomach fluids (low pH) and in atmospheric hydrometeors (mild acid and basic pH). The initial reaction associated with the oxidation/nitration of 4‐substitued phenols promoted by HONO/NO2 depends on the pH of the solution. At low pH, the initial step involves the reaction between HONO and phenol, whereas at basic conditions this involves an electron transfer from the phenoxy anion to nitrogen dioxide (NO2) producing the nitrite anion. The rate of both processes is determined by the donor capacity of the substituent at the 4‐position of the phenol, and the data obtained at pH 2.3 follow a linear Hammett‐type correlation with a slope equal to –1.23. The partition of the gaseous intermediates (NO and NO2) makes the rate of HONO‐mediated oxidation dependent on their gas–liquid distribution. At low pH, the main process is phenol oxidation, even in oxygen‐free conditions, and the presence of any 4‐substituted phenol decreases the rate of HONO auto‐oxidation.

High-resolution magic angle spinning description of the interaction states and their kinetics among basic solutes and functionalized silica materials

Modeling of the interaction is crucial to understanding and predicting chromatography. However, the complexity and variety of the grafted motifs render the creation of an accurate model overwhelmingly challenging, so that most often the classification of column separation properties is described by monitoring the retention times of carefully selected control molecules. We analyzed here the characteristics of the interplay of compounds of basic nature by 1H HRMAS NMR, which provide relevant descriptors for products with pharmaceutical properties, with chromatographic phases for Reversed Phase Liquid Chromatography. Eight grafted silica phases were selected, differing to enhance specific structural properties (monomeric and polymeric grafts, endcapping or not, carbon content, alkyl with polar embedded group or alkyl bonded chain, chemical nature of end capping, native silica). These materials were put in interaction with five basic molecules, previously chosen as probes for the evaluation of efficient base deactivated liquid stationary phases using five theoretical molecular descriptors to cover a large scale of molecular volume, polar surface area, LogP, hydrogen-bond donor capacity and finally hydrogen-bond acceptor capacity. 1H HRMAS NMR was capable of describing qualitatively a wealth of interaction states, characterized both thermodynamically and kinetically. In one case (penbutolol) up to five interaction states could be differentiated. Variable temperature experiments revealed the complexity of the retention process on grafted silica as in some cases the kinetics of the interaction is shown to slow down on increasing the temperature.

Electrochemical and spectroscopic characteristics of dissolved organic matter in a forest soil profile

Dissolved organic matter (DOM) represents one of the most mobile and reactive organic compounds in ecosystem and plays an important role in the fate and transport of soil organic pollutants, nutrient cycling and more importantly global climate change. Electrochemical methods were first employed to evaluate DOM redox properties, and spectroscopic approaches were utilized to obtain information concerning its composition and structure. DOM was extracted from a forest soil profile with five horizons. Differential pulse voltammetry indicated that there were more redox-active moieties in the DOM from upper horizons than in that from lower horizons. Cyclic voltammetry further showed that these moieties were reversible in electron transfer. Chronoamperometry was employed to quantify the electron transfer capacity of DOM, including electron acceptor capacity and electron donor capacity, both of which decreased sharply with increasing depth. FT-IR, UV-Vis and fluorescence spectra results suggested that DOM from the upper horizons was enriched with aromatic and humic structures while that from the lower horizons was rich in aliphatic carbon, which supported the findings obtained by electrochemical approaches. Electrochemical approaches combined with spectroscopic methods were applied to evaluate the characteristics of DOM extracted along a forest soil profile. The electrochemical properties of DOM, which can be rapidly and simply obtained, provide insight into the migration and transformation of DOM along a soil profile and will aid in better understanding of the biogeochemical role of DOM in natural environments.

Nutritional and antioxidant properties of Geoffroea decorticans, an Argentinean fruit, and derived products (flour, arrope, decoction and hydroalcoholic beverage)

Geoffroea decorticans, popularly known as “Chañar,” is widely distributed throughout Northwestern Argentina. Its fruit is consumed in different forms (flour, arrope, and hydroalcoholic beverage) in several Argentinean communities. The aim of this work is to quantify macronutrients and phytochemicals of G. decorticans fruit and its derived products as well as to determine its functional properties and toxicity. A high content of fiber and other phytochemicals (carotenoids, ascorbic acid and polyphenols, principally non flavonoids) were detected in Chañar flour. Since physicochemical changes that affect the functional properties of the fruit may occur during processing, different traditional foods were obtained from the fruit and their properties were studied. The phenolic compound content in different arrope types (with and without sugar added) was lower (between 3 and 18 fold) than that of Chañar flour. Condensed tannins were the dominant phenolics in the flour but in arrope without sugar they decreased 21 fold and in arrope with sugar were not detected. The content of ascorbic acid in arrope was similar to that of flour. All preparations obtained from flour and arrope showed hydrogen or electron donor capacity and were active as lipoperoxidation inhibitors. On the other hand, extracts did not show any mutagenic effect. The consumption of Chañar flour, beverage, decoction and arrope could be encouraged for their functional and nutritional properties. The exploitation of this native natural resource could be very important for regional economy.

Electron donor capacity of reducing dissolved organic matter from crop residue decomposition as probed by chronoamperometry

Reducing dissolved organic matters (RDOMs) from the anaerobic decomposition of crop residue can greatly affect the physicochemical and biological properties of soils. Electrochemical methods that can effectively protect them from oxidation and rapidly obtain results, such as differential pulse voltammetry (DPV), have been applied to qualitatively analyzing properties of RDOMs. However, the donated amount of electrons from RDOMs as a capacity factor may be more crucial for evaluating their important roles. For the first time, matured chronoamperometry (CA) was applied to quantitatively determining the electron donor capacities of RDOMs in crop residue management. The electron donor capacities of RDOMs from green manure were much higher than those from rice straw, which indicated that the former had greater effect on the redox status and reactions of soil. Chronoamperometry was proposed as a practical and effective method to quantitatively characterize RDOMs from residue decomposition.

Solvent Effects on the Dissociation Constants of Hydroxyflavones in Organic–Water Mixtures. Determination of the Thermodynamic pKa Values by UV–Visible Spectroscopy and DFT Calculations

The acid dissociation constants (pKa) of 7-hydroxyflavone, 3-hydroxyflavone and 5-hydroxyflavone, which are practically insoluble compounds in water but of great biological and physicochemical interest, were determined by UV–visible spectroscopy in ethanol–water and acetonitrile–water solutions, varying the solvent relative permittivity in the interval of 61 to 75, at constant ionic strength (0.050 mol·kg–1) and temperature (298.15 K). The pKa values of the compounds increase as the permittivity of the reaction medium decreases. Correlations were established between the pKa values and empirical parameters of the solvents, such as the relative permittivity and hydrogen-bond donor capacity. These equations allow the interpretation of the solvent effect on the acid–base equilibria and the determination of pKa values at 298.15 K in pure water. The ordering of the pKa values was 7-hydroxyflavone (7.28) < 3-hydroxyflavone (8.68) < 5-hydroxyflavone (11.75). In addition, the dissociation constants were also calculated by means of DFT methods (B3LYP/6-311+G(2d,p) level of theory), employing several thermodynamic cycles. The solvent effect on the optimized structures in the gas-phase was evaluated using the polarizable continuum model. A good agreement was observed between the theoretical and experimental pKa values. Finally, the experimental ordering in the acidity of the hydroxyflavones was explained using natural bond orbital analysis.

Experimental and theoretical studies of a new donor–acceptor Re(I) complexes using nitropolypyridil ligand. Analysis of the NLO potential response

A series of eight complexes with general structure [ARe(CO)3D]+, (A=NO2phen, NO2dppz; D=TBP, MOP, DMAP, PEPN) were synthesized and characterized by IR, NMR, UV–Vis spectroscopy and cyclic voltammetry. The donor and acceptor capacities, for the series of ligands employed, were measured in terms of two theoretical indexes, such as electrophilicity and orbital softness. It was found that, when the acceptor ligand is NO2phen, an increase of the donor strength on the ligand causes a change in the first oxidation potential and slight change in the stretching frequencies of the NO2 group, but not of the carbonyl group. This behavior is not observed when the acceptor ligand is NO2dppz. The character of the absorption band (MLCT), ILCT, etc.), and the possibility of non linear optics activity of some of the complexes was analyzed. The calculated static hyperpolarizability, β0, employing two different methods, indicates that the most promising complexes are those containing the PEPN ligand; the NLO behavior response is attributed to the enhancement of the non linear response of the PEPN ligand upon coordination to the [Re(CO)3D]+ fragment.

Visible light photodegradation of phenanthrene catalyzed by Fe(III)-smectite: Role of soil organic matter

In the present study, phenanthrene is employed as a model to explore the roles played by three soil organic matter (SOM) fractions, i.e., dissolved organic matter (DOM), humic acid (HA), and fulvic acid (FA), in its photodegradation with assistance of Fe(III)-smectite under visible-light. Slight decrease in phenanthrene photodegradation rate was observed in the presence of DOM, which is explained in terms of oxidative-radical competition between DOM and target phenanthrene molecules due to the high electron–donor capacity of phenolic moieties in DOM. On the other hand, a critic content is observed with FA (0.70mg/g) and HA (0.65mg/g). Before reaching the critic content, the removal of phenanthrene is accelerated; while after that, the photodegradation rate is suppressed. The acceleration of phenanthrene degradation can be attributed to the photosensitization of FA and HA. Due to the strong interaction between phenanthrene and the phenyl rings, however, the retention of phenanthrene on SOM–Fe(III)-smectite in the presence of high content of HA or FA is enhanced, thus slowing down its photodegradation. Those observations provide valuable insights into the transformation and fate of PAHs in the natural soil environment and open a window for using clay–humic substances complexes for remediation of contaminated soil.

Dendritic cell modification as a route to inhibiting corneal graft rejection by the indirect pathway of allorecognition

Dendritic cell (DC) modification is a potential strategy to induce clinical transplantation tolerance. We compared two DC modification strategies to inhibit allogeneic T-cell proliferation. In the first strategy, murine DCs were transduced with a lentiviral vector expressing CTLA4-KDEL, a fusion protein that prevents surface CD80/86 expression by retaining the co-stimulatory molecules within the ER. In the second approach, DCs were transduced to express the tryptophan-catabolising enzyme IDO. CTLA4-KDEL-expressing DCs induced anergy in alloreactive T cells and generated both CD4+CD25+ and CD4+CD25− Treg cells (with direct and indirect donor allospecificity and capacity for linked suppression) both in vitro and in vivo. In contrast, T-cell unresponsiveness induced by IDO+ DCs lacked donor specificity. In the absence of any immunosuppressive treatment, i.v. administration of CTLA4-KDEL-expressing DCs resulted in long-term survival of corneal allografts only when the DCs were capable of indirect presentation of alloantigen. This study demonstrates the therapeutic potential of CTLA4-KDEL-expressing DCs in tolerance induction.

Synthesis and in Vitro Antiproliferative Activity of New Phenylaminoisoquinolinequinones against Cancer Cell Lines

A variety of phenylaminoisoquinolinequinones were synthesized and tested for their antiproliferative activity against three human-tumor derived cancer cell lines. The new aminoquinones were prepared from 4-methoxycarbonyl-3-methylisoquinoline-5,8-quinone (1) via acid-induced amination and bromination reactions. Remarkable differences in antiproliferative activity were observed depending upon the location and donor capacity of the substituted phenylamino group at the quinone nucleus. The effect of the substituents on the biological activity is discussed in terms of the donor-acceptor interactions which were evaluated through the redox properties of the aminoquinones.

Structural Adaptation of Proteins to Different Biological Membranes

Transmembrane polarity profiles and distributions of different protein groups that interact directly with lipids were calculated for 3D structuresof 187 α-helical and 73 β-barrel proteins from eight types of biological membranes. The polarity profiles were represented by H-bonding donor and acceptor capacities (α and β) and polarizability parameter (π∗) calculated for protein surface. The proteins from the set have different hydrophobic thicknesses, with average values of 23.1, 27.3 and 32.5 Å for outer bacterial, inner mitochondrial and eukaryotic plasma membranes, respectively, and 29.5 to 30.6Å for endoplasmic reticulum, thylakoid and different bacterial membranes. The proteins have three distinct polarity regions: lipid head group area with peaks for positively charged groups and crystallized water (15 to 25Å from the bilayer center); interfacial “mid-polar” region with peaks for Tyr and Trp (8 to 15Å); and aliphatic hydrocarbon core (±8Å). Polarity of the core region was nearly identical for different membranes (α∼0.01, β∼0.04, π∗=0.09-0.14). Main changes in polarity occur at the level of lipid carbonyl groups (∼15±5Å), but the changes are more gradual than in DOPC bilayer. The locations and amplitudes of peaks for Trp, Tyr, and Phe are frequently asymmetric and dependent on the type of membrane. The distributions of crystallized water have two peaks at ±20Å. Head groups of crystallized lipids are shitted closer to the hydrocarbon boundary, especially in mitochondrial membrane and on the inner side of eukaryotic plasma membrane. All proteins have a peak of positive net charge at ∼20 Å on the inner side, consistent with the “positive inside” rule, except single-chain β-barrels that follow “negative inside” rule. All curves are shifted inwards in β-barrels, consistent with their smaller thickness. Computational modeling of membrane proteins can be improved using hydrophobic thicknesses and asymmetric polarity profiles for different membranes.

超高比表面积氮掺杂碳气凝胶的制备及其电化学性能

Activated N-doped carbon aerogel (N-ACA) is synthesized by the sol-gel polycondensation of resorcinol with formaldehyde using the melamine as nitrogen source, and then the carbon derivative being activated in CO2 flow. The surface morphology and porous structure are analyzed using scanning electron microscopy (SEM) and N2 adsorption at 77 K. The contained nitrogen of surface and monolith is tested by X-ray photoelectron spectroscopy (XPS) and elemental analysis. The electrochemical performances of N-dope carbon aerogels as electrodes are confirmed using constant-current charge-discharge test (GV), cyclic voltammetry (CV) and electrochemical impedance spectroscopy (EIS). It reveals that the rich porous structure and the chemical state of nitrogen functionalities have crucial effect on the electrochemical performance of the electric double-layer capacitors. The appropriate CO2 activation can increase the number of micropores and mesopores as well as the specific surface area (4082 m2g-1).Furthermore, the presence of amount of pyrrolic nitrogen is reinforced in the electron donor capacity. The specific capacitance of N-ACA electrode is up to 211.9 Fg-1 and retains about 98% after 500 charge-discharge cycles.

Linear Trifluoroethylamine RGD Peptidomimetics: Stereoselective Synthesis and Integrin αvβ3 Affinity

The Arg-Gly-Asp (RGD) tripeptide is the smallest recognition sequence for the α_vβ₃ integrin receptor. A number of nonpeptide analogues of the RGD linear sequence, some of them having improved pharmacological properties, have been proposed in the last two decades. In this study, the stereogenic trifluoroethylamine function was employed as peptide bond surrogate for the development of a new class of RGD peptide mimics. In fact, the trifluoroethylamine group was shown to behave as a peptide-bond surrogate maintaining the H-bond donor capacity of the NH peptide group and a CH(CF₃)NH backbone angle close to the native peptide bond 120°. The trifluoroethylamine function is also known to display high metabolic stability and in some cases it positively affects ligand–receptor interactions. Two linear Ψ[CH(CF₃)NH]Gly-RGD diastereoisomers were synthesized with good stereocontrol and submitted to biological assays. A remarkable loss in α_vβ₃ integrin affinity was observed for both compounds, suggesting that the bulky CF₃ moiety is not well tolerated within the α_vβ₃ binding pocket.

Preferential solvation of thiophene and furan-2-carboxaldehyde phenylhydrazone derivatives in DMSO–water and DMSO–n-octanol mixtures

The preferential solvation of thiophene- and furan-2-carboxaldehyde phenylhydrazone derivatives in DMSO–water and DMSO–n-octanol mixtures has been studied using visible absorption spectroscopy with a previous characterization of the electronic transitions by Time-Dependent Density Functional Theory (TDDFT) and solvatochromic study in several solvents with different hydrogen-bond donor capacity. The results indicate that the phenylhydrazones are preferentially solvated by clusters of DMSO–water existing in the solvent mixture and the dielectric enrichment as preferential solvation mechanism was discarded. A relation between local DMSO concentration with nitro groups and the electronegativity of the heteroatom of the five-membered ring was found. For DMSO–1-octanol mixtures, the results showed no preferential solvation.

Application of linear free energy relationships to characterizing the sorptive characteristics of organic contaminants on organoclays from water

Linear free energy relationships (LFERs) were applied to investigate the sorptive characteristics of organic contaminants (OCs) on organoclays from water. Three cetyltrimethylammonium modified montmorillonites (C-Mts) were selected as representative organoclays. The sorption coefficients (logKoc) of OCs on the C-Mts were calculated according to the results of batch sorption experiments. Then the LFER equations for OC sorption on C-Mts from water were developed. The results of this study showed that compared with bulk water, water saturated C-Mts are more polarizable, less polar and cohesive, and have stronger H-bond acceptor capacities and weaker H-bond donor capacities. The primary driving forces for the sorption of OCs from water to C-Mts can be ascribed to the weaker cohesive characteristics of C-Mts as well as the stronger nonspecific Van der Waals interaction between OCs and C-Mts. With increasing CTMA loading amount, the interaction between OCs and C-Mts increases whereas the C-Mts become more cohesive. Consequently, the sorption capacity of C-Mts first increases with CTMA loading amount and then decreases with further increased loading amount.