Three-dimensional, quantitative-structure-property-relationship study of aqueous solubility for phenylsulfonyl carboxylates using comparative-molecular-field analysis and comparative-molecular-similarity-indices analysis.

With both the comparative-molecular-field analysis (CoMFA) and the comparative-molecular-similarity-indices analysis (CoMSIA), the paper describes two five-component, three-dimensional, quantitative-structure-property-relationship (3D-QSPR) models for the aqueous solubility logSw (Sw, mol x L(-1)) of 52 phenylsulfonyl carboxylates. Two models yield the leave-one-out cross-validated correlation coefficient q2 values 0.851 and 0.821, and the conventional correlation coefficient r2 values 0.963 and 0.929, respectively. The achievement of high q2 and r2 values of the CoMFA model indicates the significance of correlation of steric and electrostatic fields with the aqueous solubility. The key features in the CoMFA contour maps are critical to trace the important properties and gain insight to the solvation mechanism of tested compounds. The quality of CoMSIA model is slightly lower than that of CoMFA in terms of q2 and r2 values. Not requiring molecular superposition, CoMSIA may be faster than CoMFA in data processing.     

Studies of 3D-quantitative structure-activity relationships on a set of nitroaromatic compounds: CoMFA,advanced CoMFA and CoMSIA

By using comparative molecular field analysis (CoMFA), advanced CoMFA and comparative molecular similarity index analysis (CoMSIA) methods, the 3D relationships between the structures of 35 nitroaromatic compounds and their toxicities have been investigated to yield statistically reliable models of considerable predictive power. In contrast to CoMFA, CoMSIA produces better results for the correlation. Moreover, the obtained CoMSIA contour maps that interpret the correlations in terms of field contributions allow physicochemical properties relevant for binding to be easily mapped back onto molecular structures, and thus elucidate structural features among ligands that are responsible for toxicities. Besides, most of the highlighted regions in CoMSIA and CoMFA contour maps are mirrored by features in the surrounding environment. Thereby, CoMFA and CoMSIA both help to give explanations of the toxic mechanism of tested compounds.     

3D QSAR studies of dioxins and dioxin-like compounds using CoMFA and CoMSIA

In the present study we have performed comparative molecular field analysis (CoMFA) and comparative molecular similarity indices analysis (CoMSIA) on structurally diverse ligands of Ah (dioxin) receptor to explore the physico-chemical requirements for binding. All CoMFA and CoMSIA models have given q(2) value of more than 0.5 and r(2) value of more than 0.84. The predictive ability of the models was validated by an external test set, which gave satisfactory predictive r(2) values. Best predictions were obtained with CoMFA model of combined modified training set (q(2) = 0.631, r(2) = 0.900), giving predictive residual value = 0.02 log unit for the test compound. Addition of CoMSIA study has elucidated the role of hydrophobicity and hydrogen bonding along with the effect of steric and electrostatic properties revealed by CoMFA. We have suggested a model comprises of four structurally different compounds, which offers a good predictability for various ligands. Our QSAR model is consistent with all previously established QSAR models with less structurally diverse ligands.     

多溴联苯醚与雌激素受体作用的CoMFA／CoMSIA研究

以多溴联苯醚类化合物的ER亲合力为生物活性指标，运用基于配体结构信息的CoMFA／CoMSIA方法，模拟该类化合物与雌激素受体的结合作用机制，结果表明，这些结构类似化合物中存在的不同受体作用模式，需要结合基于受体功能区结构的QSAR方法进一步探讨。     

Acute toxicity of substituted phenols to Rana japonica tadpoles and mechanism-based quantitative structure-activity relationship (QSAR) study.

Acute 12 h and 24 h lethal toxicity (12 h-LC50 and 24 h-LC50) of 31 substituted phenols to Rana japonica tadpoles was determined. Results indicate that toxicity of phenols to tadpoles varied only slightly with length of exposure and the 12-h test could serve as surrogate of the 24-h test. A mechanism-based quantitative structure-activity relationship (QSAR) method was employed and 1-octanol/water partition coefficient (log K(ow))-dependent models were developed to study different modes of toxic action. Most phenols elicited their response via a polar narcotic mechanism and an excellent logK(ow)-dependent model was obtained. Soft electrophilicity and pro-electrophilicity were observed for some phenols and a good log K(ow)-dependent model was also achieved. Additionally, the significant dissociation of carboxyl on benzoic acid derivatives sharply reduced their toxicity. A statistically robust QSAR model was developed for all studied compounds with the combined application of log K(ow), energy of lowest unoccupied orbital (E(lumo)), heat of formation (HOF) and the first-order path molecular connectivity dices (1chi(p)).     

Reverse quantitative structure-activity relationship for modelling the sorption of esfenvalerate to dissolved organic matter. A multivariate approach

The sorption of the pyrethroid, esfenvalerate, to the dissolved and/or dispersed fraction of eight different natural humic compounds has been investigated. The dissolved organic matters (DOMs) included in this study originate from ground water, soil pore water, and surface waters. Sorption was modelled at DOM concentration levels where equilibrium partitioning of esfenvalerate between DOM and the aqueous bulk phase prevails. The inherent characteristics of the eight different humic materials, quantified in the preceding paper by Thomsen et al. (2002, this issue (PII: S0045-6535(02)00335-1)), have been used as explanatory variables for modelling this equilibrium partitioning. Using a reverse QSAR approach based on by projection-into-latent-structure regression (PLS-R) inherent sorbent properties determining for the sorption affinity of esfenvalerate to DOM were analysed. For all humic substances a decrease in the DOM-normalised equilibrium-partitioning coefficient, K_DOM, with increasing concentration of DOM was observed. Significant variations in K_DOM values, as function of the inherent characteristics of the individual humic substances, were found at DOM concentrations of 75 and 100 ppm, respectively. The latter is a strong indication of variations in sorption mechanisms of esfenvalerate to DOM of varying inherent properties. Groupings in the principal property space quantifying DOMs may indicate that separate models are needed for quantifying the equilibrium partitioning to different classes of DOM.     

Three-dimensional quantitative structure activity relationship (3D-QSAR) analysis for in vitro toxicity of chlorophenols to HepG2 cells

In the present paper, comparative molecular field analysis (CoMFA) and comparative molecular similarity indices analysis (CoMSIA) were applied to investigate two 3D-QSAR models for the cytotoxicity of chlorophenols. These models have evaluated the intensity of chlorophenols' toxicity on HepG2 cells in vitro. The CoMFA model has both high consistency and predictability. The contribution of the electrostatic field to biological activity is greater than that of the steric field. The CoMSIA model used in this study includes two fields, one is hydrophobic field, and the other is electrostatic field. The relative contribution of them is 0.789:0.211. Consisted with the CoMFA model, the CoMSIA electrostatic filed also plays a dominant role. The CoMFA and CoMSIA contour maps significantly elucidated that the electrostatic field is more important than the other fields and might be one of the reasons resulting in potential reactive mechanism involved in cell proliferation inhibition.     

Mechanism-based quantitative structure-activity relationships for the inhibition of substituted phenols on germination rate of Cucumis sativus

Comparative inhibition activity (GC50) of 42 structurally diverse substituted phenols on seed germination rate of Cucumis sativus was investigated. Quantitative structure-activity relationships (QSARs) were developed by using hydrophobicity (1-octanol/water partition coefficient, logKow) and electrophilicity (the energy of the lowest unoccupied molecule orbital, Eluma) for the toxicity of phenols according to their modes of toxic action. Most phenols elicited their response via a polar narcotic mechanism and a highly significant log Kow-based model was obtained (GC50 = 0.92 log Kow + 1.99, r2 0.84, n = 29). The inclusion of E(lumo) greatly improved the predictive power of the polar narcotic QSAR (GC50 = 0.88 log Kow - 0.30E(lumo) + 1.99, r2 = 0.93, n = 29). pKa proved to be an insignificant influencing factor in this study. Poor correlation with hydrophobicity and strong correlation with electrophilicity were observed for the nine bio-reactive chemicals. Their elevated toxicity was considerably underestimated by the polar narcotic logKow-dependent QSAR. The nine chemicals consist of selected nitro-substituted phenols, hydroquinone, catechol and 2-aminophenol. Their excess toxic potency could be explained by their molecular structure involving in vivo reaction with bio-macromolecules. Strong dissociation of carboxyl group of the four benzoic acid derivatives greatly decreased their observed toxicity. In an effort to model all chemicals including polar narcotics and bio-reactive chemicals, a response-surface analysis with the toxicity, logKow and E(lumo) was performed. This resulted in a highly predictive two-parameter QSAR for most of the chemicals (GC50 = 0. 70 logKow - 0.66E(lumo) + 2.17, r2 = 0.89, n = 36). Catechol and 2,4-dinitrophenol proved to be outliers of this model and their much high toxicity was explained.     

Three-dimensional quantitative structure activity relationships of quorum-sensing and biofilm inhibitors in gram-negative bacteria

Thirty N-acyl homoserine lactone (AHL) analogs with variable antibacterial activity and displaying inhibition of biofilm formation were selected to develop models for establishing three-dimensional quantitative structure-activity relationships (3D-QSAR). Comparative molecular field analysis (CoMFA) and comparative similarity indices analysis (CoMSIA) were carried out to determine the optimum structural requirements for selectivity and potency of quorum-sensing and bacterial biofilm inhibition. The best CoMFA model predicted a q2 value of 0.519 and an r2 value of 0.984 and revealed that electrostatic and steric properties play a significant role in potency and selectivity. The CoMSIA model predicted a q2 value of 0.411 and an r2 value of 0.938 based on a combination of steric, electrostatic, and hydrophobic effects. The analysis of the contour maps from each model provide insight into the structural requirements for increasing the activity of a compound. Consequently, manipulating the chemical and physical properties of substituted acyl groups on the homoserine lactone moiety can provide important information toward enhancing the antibacterial properties of the target chemical compound.     

Three-dimensional quantitative structure activity relationships of quorum-sensing and biofilm inhibitors in gram-negative bacteria

Thirty N-acyl homoserine lactone (AHL) analogs with variable antibacterial activity and displaying inhibition of biofilm formation were selected to develop models for establishing three-dimensional quantitative structure-activity relationships (3D-QSAR). Comparative molecular field analysis (CoMFA) and comparative similarity indices analysis (CoMSIA) were carried out to determine the optimum structural requirements for selectivity and potency of quorum-sensing and bacterial biofilm inhibition. The best CoMFA model predicted a q² value of 0.519 and an r² value of 0.984 and revealed that electrostatic and steric properties play a significant role in potency and selectivity. The CoMSIA model predicted a q² value of 0.411 and an r² value of 0.938 based on a combination of steric, electrostatic, and hydrophobic effects. The analysis of the contour maps from each model provide insight into the structural requirements for increasing the activity of a compound. Consequently, manipulating the chemical and physical properties of substituted acyl groups on the homoserine lactone moiety can provide important information toward enhancing the antibacterial properties of the target chemical compound.     

Molecular orbital studies on brominated diphenyl ethers. Part II--reactivity and quantitative structure-activity (property) relationships

Polybrominated diphenyl ethers (PBDEs) are widely used as flame retardants and are increasingly turning up in the environment. Their structural similarities to polychlorinated biphenyls and thyroid hormones suggest they may be a risk to human health. The present study examines the reactivity of brominated diphenyl ethers (BDEs) on the basis of the electronic structures as calculated by semiempirical AM1 self-consistent field molecular orbital (SCF-MO) method. Frontier orbital energies were used to elucidate the reactivity of BDEs in electrophilic, nucleophilic and photolytic reactions. From an examination of the frontier electron densities, the regioselectivity, or orientation, of metabolic reactions of BDEs was predicted. Furthermore, satisfactory quantitative structure-activity (property) relationship (QSAR and QSPR) models were derived to calculate gas chromatographic and ultraviolet spectral properties and luciferase induction activities from the AM1-computed electronic parameters.     

Study on acute toxicity and structure-activity relationship of zebrafish (Danio rerio) exposed to naphthoquinones

In this paper, we evaluated the acute toxicity of five naphthoquinone compounds, expressed as median lethal concentration at 96 h (LC₅₀) using zebrafish as a model. The five compounds were classified as harmful or very toxic. The Gaussian method was used to calculate the quantitative-chemical parameters of each compound. Based on the structure-activity relationship analysis, the interaction between the naphthoquinones and the target is likely mediated by 1-carbonyl and the hydrophobic fraction substituted in α -position of naphthoquinone via hydrogen bonding and hydrophobic interactions. Our results provide a foundation for evaluating the aquatic ecological risk and the mode of action of naphthoquinones in the environment.