Designing Artemisinins with Antimalarial Potential, Combining Molecular Electrostatic Potential, Ligand-Heme Interaction and Multivariate Models

Artemisinins tested against W-2 strains of malaria falciparum are investigated with molecular electrostatic potential (MEP), in an attempt to identify key features of the compounds that are necessary for their activities, as well as to investigate likely interactions with the receptor in a biological process and to use that information to propose new molecules. In order to discover the best geometry involving the ligand-receptor complexes (heme) studied and help in the proposition of the new derivatives, molecular simulations of interactions between the most negative charged region around the peroxide and heme locates (the ones around the Fe2+ ion) were carried out. In addition, PCA (principal components analysis), HCA (hierarchical cluster analysis), SDA (stepwise discriminant analysis), and KNN (K-nearest neighbor) multivariate models were employed to investigate which descriptors are responsible for the classification between the higher and lower antimalarial activity of the compounds, and also this information was used to propose new potentially active molecules. The information accumulated in studies of MEP, molecular docking, and multivariate analysis supported the proposal of new structures with potential antimalarial activities. The multivariate models constructed were applied to the new structures and indicated numbers 19 and 20 as the most prominent for syntheses and biological assays.

Surface Electrostatic Potentials of Polychlorinated Dibenzo-p-dioxins and Their Applications in the Quantitative Structure-properties Relationships

Polychlorinated dibenzo-p-dioxins（PCDDs） are a group of important persistent organic pollutants.They are highly toxic and persistent in environment.In the present study,geometrical optimization and electrostatic potential calculations have been performed for 75 PCDD congeners and dibenzo-p-dioxin（DD） at the HF/6-31G＊ level of theory.A number of statistically based parameters have been extracted.Linear relationships between vapor pressures（logpL）,aqueous solubilities（logSw）,n-octanol/water partition coefficients（logKow） of PCDDs and structural descriptors have been established by stepwise linear regression analysis.The result shows that the quantities derived from the surface electrostatic potentials Vmin,Π,and Vs,av＋,together with Vmc（the molecular volume） and ELUMO（the energy of the lowest unoccupied molecular orbital） can be well used to express the quantitative structure-property relationships of PCDDs.Predictive capabilities of the models have also been demonstrated by leave-one-out cross-validation with the cross-validated correlation coefficient（Rcv） above 0.97.Based on these QSPR models,the predicted values have been presented for those PCDD congeners whose experimentally determined physicochemical properties are unavailable.

Theoretical Study on Molecular Electrostatic Potential of C_(78)

Density functional theory （DFT） was applied at the B3LYP/6-31G^＊ level to investigate the relative stability of the five fullerene isomers as well as the anions of C78. Full geometry optimization was carried out and distributions of electrostatic potential were calculated. The results showed that the C78（D3h′） cage was the most stable for C78^q-（ q = 2, 4, 6）, and the potential minimum Vmin（r） inside the sphere of C78（Dzh′） was the biggest one among the five isomers of C78. So C78（Dzh′） were electrons from the scandium atoms that were easier to accept than the other four isomers. On the other hand, MEP maps inside the sphere of C78（Dzh′） had three minima near the three vertexes. Each vertex was formed by the intersection of the three hexagons. Our results allowed a possible explanation for the bonding between the scandium atoms and the fullerene cage.

Friction Sensitivity of Nitramines. Part Ⅳ:Links to Surface Electrostatic Potentials

The friction sensitivity(FS) of five aliphatic linear and eight cyclic nitramines has been determined and correlated with DFT B3LYP/6-31-G(d,p) // 6-311+G(d,p) positive(VS,max) and negative(VS,min) extremes of molecular surface electrostatic potentials VS(r).While there is an ambiguous relationship between the VS,max values and FS values,the decrease of FS is connected(more or less) with increase in VS,min values.

QSPR of Thermal Stability of Nitroaromatic Explosives Using Theoretical Descriptors Derived from Electrostatic Potentials on the Molecular Surface

In the present study,geometrical optimization and electrostatic potential calcula-tions have been performed for 22 nitroaromatic compounds at the HF/6-31G level of theory.A number of statistically based parameters have been obtained.Linear relationship between the decomposition enthalpy（taken as a macroscopic property related to explosibility） of nitroaromatic compounds and the structural descriptors have been established by multiple regression method.The result shows that the quantities derived from electrostatic potentialsΣ V sind＋,,Vsind- and Vs,max can be well used to express the quantitative structure-decomposition enthalpy relationship of nitroa-romatic compounds,which proves the general applicability of this parameter set to a great extent.Good predictive capabilities have also been demonstrated.

Theoretical Study of the Molecular Electrostatic Potential of C_(50)

Density functional theory （DFT） calculations on three lower energy isomers of C50 were carried out at the B3LYP/6-31G＊ level. Of the three isomers, two have D5h symmetry （a singlet state and a triplet state） and the other one has D3 symmetry. The optimized configurations and electrostatic potential distributions have been obtained. The calculated results show that potential minima Vmin（r） inside the sphere occur at the center of the sphere. The most negative value of the effective Mulliken atomic charge and the largest regions with the most negative MEP outside the sphere are localized in the neighborhood of pentagon-pentagon vertex fusions. They constitute the most probable active sites in chemical reactions. Our results offer a possible explanation for protonation and alkylation of C50 fullerene.

Separation of Aromatic Carboxylic Acids in IC and the Study on the Relationship Between Retention Behavior and Electrostatic Potential

A method has been developed for separation of 20 kinds of aromatic carboxylic acid using anion-exchange chromatography. A Dionex IonPac AS9-HC guard column （250mm×2mm） was used with a 9mmol/L sodium carbonate solution containing 50% （v/v） acetonitrile as eluent. A set of retention time data has been obtained using a conductivity detector DS6. Furthermore, geometrical optimization and electrostatic potential calculation of 20 kinds of aromatic carboxylic acid have been performed at the HF/6-31G＊ level of theory. A number of statistically-based parameters derived from molecular surface electrostatic potential have been obtained. Linear relationship between retention time and structural parameters has been established by multiple regression method. The result shows that parameters derived from electrostatic potential Vs ＋, Vs -, П together with the dipole moment μ can be well used to express the quantitative structure-retention time of this kind of aromatic carboxylic acid. Good predictive capability has also been demonstrated. The result has provided a framework which further proves the general applicability of this electrostatic potential parameter set to a great extent,and with which the ion chromatographic adsorption mechanism can be investigated.

Development of a Heavy Ion Bearn Probe for Measuring Electrostatic Potential Profile and Its Fluctuation in LHD

A heavy ion beam probe （HIBP） using a 3-MV tandem accelerator has been installed on large helical device （LHD）. Electrostatic potential in core plasma can be measured under the toroidal magnetic field strength of up to 3 T. By using the HIBP, the transition of potential profiles from electron-root to ion^root is observed in core plasmas during ramp-up of the electron density. Potential fluctuations are also measured electron cyclotron current drive （ECCD）. Two kind of characteristic fluctuations are observed. One is a reversed-shear-induced Alfv^n eigenmode （RSAE）, whose frequency varies during the evolution of the rotational transform profile, and the other is with a constant geodeisc acoustic mode （GAM） frequency.

Effect of Residue Mutation on the Electrostatic Potential in EcClC

The effect of mutation of strongly conserved porelining residues in the chloride channel EcClC on the electrostatic potential and binding free energy of the chloride ion was studied using explicit protein-membrane structures. Electrostatic potential distribution and binding free energy of the chloride ion at different binding sites in the wild-type and mutated EcClC were calculated with APBS. The potential data reveal that the electrostatic potential around the selectivity filter, especially around the site Sext and Scen becomes more negative as the residue R147 was mutated to C147. The electrostatic binding free energy shows that the binding free energy of the chloride ion at all binding sites becomes more positive as R147 was mutated. It follows that mutation of R147 decreases ion stabilization at binding sites and affects channel＇s gating.

Surface Electrostatic Potentials of Polychlorinated Dibenzofurans and Their Applications in Quantitative Structure-toxicity Relationships

Polychlorinated dibenzofurans (PCDFs) represent an important kind of serious pollutant. They are highly toxic and persistent in environment. In this paper, geometrical optimizations and subsequent calculations of electrostatic potentials (ESPs) on molecular surface have been performed for all 135 PCDF congeners at the HF/6-31G* level. The effects of substitution value and variation of substitution position upon the surface ESPs have been discussed. A series of statistic-based structural descriptors derived from the surface ESPs have been calculated. For some PCDF congeners, linear relationships between aryl hydrocarbon receptor (AhR) biding affinity and aryl hydrocarbon hydroxylase (AHH) induction potency as well as theoretical descriptors have been established by multiple linear regression method. It appears that the quantities derived from the surface ESPs, Vs,min, Vs , VS +, σ+ and Nvmin, 2 together with the molecular surface area and the energy gap between HOMO and LUMO can be well used to express the quantitative structure-toxicity relationships of PCDFs.

QSPR Studies on the Physicochemical Properties of Polychlorinated Diphenyl Sulfides——The Application of Theoretical Descriptors Derived from Electrostatic Potentials on Molecular Surface

Based on the relationship between the quantitative structure and property（QSPR） of organic compounds, the surface electrostatic potential parameters of 29 polychlorinated diphenyl sulfides（PCDPSs） with experimental values were calculated and extracted, and Multiple Linear Regression（MLR） was used to model the linear relationship between the physicochemical properties（octanol/water partition coefficient, high performance liquid chromatography capacity factor） and molecular structure parameters of PCDPSs. The result shows that the main factors that affect the n-octanol/water partition coefficient and high performance liquid chromatography capacity factor are respectively the number of chlorin atoms substituted on the benzene ring（NCl） and the lowest unoccupied molecular orbital energy（ELUMO）. Secondly, there are also molecular surface electrostatic potentials. This indicates that the molecular surface electrostatic potentials can effectively express the quantitative relationship between the physicochemical properties of PCDPSs and their molecule descriptions. The QSPR models established have strong stability and predictive ability. This also has proved the applicability of molecular surface electrostatic potential parameters in QSPR of PCDPSs.

Critical Role of Molecular Electrostatic Potential on Charge Generation in Organic Solar Cells

Revealing the charge generation is a crucial step to understand the organic photovoltaics. Recent development in non-fullerene organic solar cells （OSCs） indicates efficient charge separation even with negligible energetic offset between the donor and acceptor materials. These new findings trigger a critical question concerning the charge separation mechanism in OSCs, traditionally believed to result from sufficient energetic offset between the polymer donor and fullerene acceptor. We propose a new mechanism, which involves the molecular electrostatic potential, to explain efficient charge separation in non-fullerene OSCs. Together with the new mechanism, we demonstrate a record efficiency of -12% for systems with negligible energetic offset between donor and acceptor materials. Our analysis also rationalizes different requirement of the energetic offset between fullerene-based and non-fullerene OSCs, and paves the way for further design of OSC materials with both high photocurrent and high photovottage at the same time.

Determination of electrostatic parameters of a coumarin derivative compound C_(17)H_(13)NO_3 by x-ray and density functional theory

This work is devoted to the experimental determination of the electrostatic properties of the molecular 4-methyl-7-（salicylidene amino） coumarin（C17H13NC3） using high resolution x-ray diffraction data. The experimental results are compared with those obtained theoretically from calculation type ab initio. The experimental investigation is carried out using the molecular electron charge density distribution based on the multipolar model of Hansen and Coppens. However the theoretical calculations are conducted by using the molecular orbital B3 LYP method and the Hartree-Fock（HF） approximation with the basis set 6-31G（d,p） implemented in the Gaussian program. In addition to the structural analysis,the thermal agitation is also analyzed in terms of rigid blocks to ensure a better precision of the results. Subsequently, the electrostatic atomic and molecular properties such as the net charges, the molecular dipolar moment to highlight the nature of charge transfer existing within the molecule studied are derived. Moreover, the obtained electrostatic potential enables the localization of the electropositive and the electronegative parts of the investigated molecule. The present work reports in detail the obtained electrostatic properties of this biologically important molecule.

A QSRR Study on the Relative Retention Time of Halogenated Methyl-phenyl Ethers

Halogenated methyl-phenyl ethers （anisoles） are ubiquitous organic compounds in the environment. In the present study, geometrical optimization and electrostatic potential calculations have been performed for 42 halogenated anisoles at the HF/6-31 G^＊ level. A number of statistically based parameters have been obtained. By multiple regression method, linear relationships between the gas-chromatographic relative retention time （RRT） and structural descriptors have been established for the training set of 32 halogenated anisoles. The result showed that the parameters derived from electrostatic potentials （ESPs） together with the molecular volume （Vmc） could be well used to express the quantitative structure-RRT relationships of halogenated anisoles. The best two-variable regression model gives a correlation coefficient of 0.980 and a standard deviation of 0.07, and the leave-one-out cross-validated correlation coefficient is 0.975. The goodness of the model has been further validated through exploring the predictive power for the testing set of 10 halogenated anisoles.

DFT Studies on Non-IPR C_(68) and Endohedral Fullerene Sc_3N@C_(68)

Density functional theory （DFT） calculations on two isomers of C68 with the minimal number of fused pentagon pairs, its anions and Sc3N as well as Sc3N@C68 （6140） metallofullerene were carded out at the B3LYP/6-31G^＊ level. The optimized configurations and electrostatic potential distributions have been obtained. The calculated results show that the electrostatic potentials of C68 （6140） inside the sphere have three minima in the middle of the double bonds at fusion of two hexagonal rings. In contrast, potential minimum Vmin（r） of C68 （6275） inside the sphere occurs at the center of the sphere. Concerning the two isomers of C68, the largest regions with the most negative MEP outside the sphere are both localized in the neighborhood of pentagon-pentagon vertex fusions. They constitute the most probable active sites in chemical reactions. Our results present a reasonable explanation for the bonding between scandium atoms and fullerene cage.

Prediction of Infinite Dilution Activity Coefficients of Halogenated Hydrocarbons in Water

Geometrical optimization and electrostatic potential calculations have been performed for a series of halogenated hydrocarbons at the HF/Gen-6d level. A number of electrostatic potentials and the statistically based structural descriptors derived from these electrostatic potentials have been obtained. Multiple linear regression analysis and artificial neural network are employed simultaneously in this paper. The result shows that the parameters derived from electrostatic 2 potentials σtot^2, V s and ∑ Vs^＋, together with the molecular volume （Vine） can be used to express the quantitative structure-infinite dilution activity coefficients （γ^∞） relationship of halogenated hydrocarbons in water. The result also demonstrates that the model obtained by using BFGS quasiNewton neural network method has much better predictive capability than that from multiple linear regression. The goodness of the model has been validated through exploring the predictive power for the external test set. The model obtained via neural network may be applied to predict γ^∞ of other halogenated hydrocarbons not present in the data set.

Prediction of Infinite Dilution Activity Coefficients of Alcohol and Ether Organic Compounds in Water

Based on QSPR of alcohol and ether organic compounds in water,geometrical optimization and electrostatic potential calculations were performed at the HF/6-31G＊ level for 73 alcohol and ether organic compounds.Linear relationships between infinite dilution activity coef-ficient（lnγ∞） of alcohols and ethers in water and theoretical descriptors of the molecular structure were established by multiple regression method.The result shows that the parameters derived from molecular electrostatic potential together with molecular surface area can be preferably used to express the quantitative structure-lnγ∞ relationship of alcohols and ethers in water.This reveals that this model has good predictive capabilities（RCV=0.969）.The molecular electrostatic potential has also been proved to have the general applicability in QSPR model of alcohol and ether organic compounds about γ∞ in water.The QSPR model established may provide a new powerful method for predicting γ∞ of organic compounds in aqueous systems.

Predictive and Comparative Study of Chromatographic Retention Index for 75 Chloronaphthalene Congeners

Chloronaphthalenes （PCNs, polychlorinated naphthalenes） are a group of persistent environmental pollutants. In the present study, geometrical optimization and electrostatic potential calculations have been performed for all 75 PCNs at the HF/6-31G^＊ level of theory. A number of statistic based parameters have been extracted. Linear relationships between gas-chromatographic retention index （RI） of 62 PCNs in a non-polar column （DB-5） and the structural descriptors have been established by stepwise multiple regression technique. The result shows that two quantities derived from electrostatic potential on molecular surface, ∑Vs- and σ＋^2, together with the number of chlorine （ NCl ） and the energy of the highest occupied molecular orbital （EHOMO） can be well used to express the quantitative structure-retention relationship （QSRR） of PCNs. Predictive capability of the model has been demonstrated by leave-one-out cross-validation with the cross-validated correlation coefficient （Rcv^2） of 0.997, and further compared with the results from similar researches published recently. Furthermore, when splitting the 62 PCNs into training and validation sets in the ratio of 2：1, a similar treatment yields an equation of almost equal statistical quality and very similar regression coefficients, validating the robustness and prediction capability of our model. The QSRR model established may provide a new powerful method for predicting chromatographic properties of polychlorinated naphthalenes.

Comparison of Molecular Properties (Stabilities, Reactivity and Interaction) of Manzamenones and Two Antimalarial Drugs (Quinine and Artemisinin) Using Mixed Method Calculations (ONIOM) and DFT (B3LYP)

Malaria is a real public health problem. It’s one of the pathologies that mobilize the scientific community. Resistance to existing treatments is the basis for the search for new treatments. Some molecules such as Manzamenones have shown important antimalarial properties. These molecules belong to the family of atypical fatty acid derivatives. This work presents the relative stabilities, some reactivity properties and the privileged sites of interaction by hydrogen bond of fourteen Manzamenones and two antimalarial drugs: quinine and Artemisinin. These analyses were performed using quantum chemical calculations. We employed the two-layer ONIOM calculation method;namely ONIOM (B3LYP/6-311++G (d, p): AM1) for the fourteen Manzamenones. The geometries of the two antimalarials are calculated at B3LYP/6-311++G (d, p). The electrostatic potential (ESP) calculation of all molecules is done at the B3LYP/6-31++G (d, p) level. The formation processes of the molecules are discussed from the thermodynamic quantities we have calculated. The relative stabilities, the energies of the frontier orbitals, the energy gaps, the dipole moment, etc., are evaluated and discussed. The electrostatic potential at the molecular surface has been used to identify the sites favorable to the formation of hydrogen bonds.

Mixed ion and electron transport theory and application in solid oxide conductors

Mixed ions and electron conductors(MIECs)are an important family of electrocatalysts for electrochemical devices,such as reversible solid oxide cells,rechargeable metal-air batteries,and oxygen transport membranes.Concurrent ionic and electronic transports in these materials play a key role in electrocatalytic activity.An in-depth fundamental understanding of the transport phenomena is critically needed to develop better MIECs.In this brief review,we introduced generic ionic and electronic transport theory based on irreversible thermodynamics and applied it to practical oxide-based materials with oxygen vacancies and electrons/holes as the predominant defects.Two oxide systems,namely CeO_(2)-based and La CrO_(3)-based materials,are selected as case studies to illustrate the utility of the transport theory in predicting oxygen partial pressure distribution across MIECs,electrochemical electronic/ionic leakage currents,and the effects of external load current on the leakage currents.