QSAR study on toxicity to aqueous organisms using the PI index

We have attempted to develop quantitative structure-toxicity relationships (QSTRs) to predict hydrophobicity (logP) as well as toxicity (pEC50 microm) of benzene derivatives using recently introduced Padmakar-Ivan (PI) index. The results have shown that both logP as well as pEC50 of benzene derivatives can be modelled excellently in multiparametric models in that the PI index and some indicator parameters are involved. The predictive ability of the models is discussed on the basis of the cross-validation method. The superiority of the PI index over several other topological indices is critically examined.     

QSAR study on bioconcentration factor (BCF) of polyhalogented biphenyls using the PI index

Attempt has been made to estimate the accuracy, predictive power, and domain of application of the PI (Padmakar-Ivan) index for modeling bioconcentration factor (BCF) of polyhalogenated biphenyls. Relative potential of PI index is investigated by comparing the results obtained using this index with those obtained from Wiener (W) and Szeged (Sz) indices. In addition, attempt has also been made to model hydrophobicity/lipophilicity (logP) of the polyhalogenated biphenyls using these indices. It was observed that these distance-based topological indices gave better results for modeling log BCF than logP.     

Chemicobiological interactions and the use of partition coefficients in their correlation

Using octanol/water partition coefficients as an operational definition of hydrophobicity, 70 examples are given in which the hydrophobic interactions of organic compounds with themselves (in micelles) with macromolecules or with biological systems can be quantitatively correlated by the expression: log RBR = a log P + b. In this expression RBR is a binding constant or a relative biological response, P is the octanol/water partition coefficient and a and b are constants obtained via the method of least squares. These results are strong support for the utility of log P in the correlation of hydrophobic interactions. They also illustrate the extremely wide range of processes in which hydrophobic bonding plays a critical role.     

Rapid determination of logarithmic partition coefficients between n-octanol and water using micellar electrokinetic capillary chromatography

Micellar electrokinetic capillary chromatography (MECC) was evaluated as a rapid screening tool for the determination of logarithmic partition coefficients between n-octanol-water (logP_ow). The technique is performed by electrochromatographing a mixture of standards of known log P_ow. The logarithmic capacity factor of each standard was plotted against its log P_ow to form a linear calibration curve for a given set of chromatographic conditions. The log P_ow of an unknown is calculated by using its chromatographically determined capacity factor and extracting the log P_ow value from the calibration curve. The method was evaluated with a set of model compounds with known log P_ow. The accuracy of the method was examined and found to be within the limits required for screening purposes. The correlation of log P_ow values determined using HPLC and MECC for some novel compounds was examined. This technique allows the screening of log P_ow at a rate of four samples per hour with minimal sample requirements (<μg) and with extremely small solvent waste generated.     

QSAR study on benzenesulphonamide carbonic anhydrase inhibitors: topological approach using Balaban index

QSAR study on benzenesulphonamide carbonic anhydrase inhibitors has been made using the most discriminatory Balaban index (J). The regression analysis has shown that even in monoparametric regression this index gave excellent results. Furthermore, using the combination of the Balaban Index (J) with the first-order Randic connectivity index ((1)chi) and indicator parameters, tremendous improvement in the statistics has been observed. The results are critically discussed on the basis of regression data and cross-validation parameters.     

Effect of octanol:water partition coefficients of organophosphorus compounds on biodistribution and percutaneous toxicity

Knowledge of partition coefficient (log P) data can play a critical role in understanding the pharmacokinetic and pharmacodistributive properties of toxic organophosphorus (OP) compounds. Using a recently published gas chromatographic method, the octanol:water log P values for the compounds tabun (GA), sarin (GB), cyclosarin (GF), and O-ethyl-S-(2-diisopropylaminoethyl) methylphosphonothiolate (VX) were determined to be 0.384 +/- 0.033, 0.299 +/- 0.016, 1.038 +/- 0.055, and 0.675 +/- 0.070, respectively. Based on these data, the log P value of the fluorophosphonate fragment, common to GB, soman (GD), and GF, was determined to be -2.256 +/- 0.273. The predictive value for absorption and distribution of the determined log P values was compared to measured values. The time to onset of local fasciculations (47.3, 29.0, 8.8, 8.5, and 6.3 min, respectively) in guinea pigs exposed percutaneously to equilethal doses of GA, VX, GF, GB, or GD was used as an indicator of dermal penetration. There was a good correlation (r = 0.95) between the measured log P value and the rate of onset of local fasciculations. Assuming a direct correspondence, equilibrium tissue:blood log P may be estimated from octanol:water log P. Comparison of the estimated and directly measured tissue:blood log P revealed a correlation of 0.8 for GD in liver, muscle, and adipose tissue. Our results demonstrate the use of log P data to both predict absorption and determine the distribution of OP compounds in tissues. This facilitates further estimates of in vivo OP effects from in vitro experiments.     

A model for the prediction of partition coefficients in aqueous two-phase systems.

A mathematical model has been developed to predict partition coefficients for aqueous two-phase systems. The model is based on a previously-developed equation for partitioning which arises from an osmotic pressure viral expansion. The model suggests that the properties of importance are the concentration difference of one of the phase-forming components, such as a polymer, and the hydrophobicity of the solute relative to the hydrophobic-hydrophilic difference between the two phases. Several two-phase systems have been studied, with a particular emphasis on the poly(ethylene glycol)/magnesium sulfate system. Numerous solutes, including peptides, were used in this system and their partition coefficients show good agreement with the model.     

Partitioning of triphenylalkylphosphonium homologues in gel bead-immobilized liposomes: chromatographic measurement of their membrane partition coefficients

Unilamellar liposomes of small or large size, SUVs and LUVs, respectively, were stably immobilized in the highly hydrophilic Sepharose 4B or Sephacryl S-1000 gel beads as a membrane stationary phase for immobilized liposome chromatography (ILC). Lipophilic cations of triphenylmethylphosphonium and tetraphenylphosphonium (TPP+) have been used as probes of the membrane potential of cells. Interaction of TPP+ and triphenylalkylphosphonium homologues with the immobilized liposomal membranes was shown by their elution profiles on both zonal and frontal ILC. Retardation of the lipophilic cations on the liposome gel bed was increased as the hydrophobicity of the cations increased, indicating the partitioning of lipophilic cations into the hydrocarbon region of the membranes. The cations did not retard on the Sepharose or Sephacryl gel bed without liposomes, confirming that the cations only interact with the immobilized liposomes. Effects of the solute concentration, flow rate, and gel-matrix substance on the ILC were studied. The stationary phase volume of the liposomal membranes was calculated from the volume of a phospholipid molecule and the amount of the immobilized phospholipid, which allowed us to determine the membrane partition coefficient (KLM) for the lipophilic cations distributed between the aqueous mobile and membrane stationary phases. The values of KLM were generally increased with the hydrophobicity of the solutes increased, and were higher for the SUVs than for the LUVs. The ILC method described here can be applied to measure membrane partition coefficients for other lipophilic solutes (e.g., drugs).     

Predicting the partition coefficients of a recombinant cutinase in polyethylene glycol/phosphate aqueous two-phase systems

A model for the prediction of protein partition coefficients in aqueous two-phase systems has been developed. This model accounts for both charge-independent and electrostatic effects. The determination of nonelectrostatic effects was based on the model of Eiteman and Gainer for uncharged solutes while the electrostatic contribution was computed using TITRA, a program that uses a continuum electrostatic model to treat charge interactions in proteins and considers the effect of pH and ionic strength. The partition coefficients of Fusarium solani pisi recombinant cutinase have been satisfactorily predicted in polyethylene glycol (PEG) 1000 and phosphate aqueous two-phase systems at a pH range of 6.0-9.0. The model failed to predict the enzyme partitioning behavior at pH 4.5. (c) 1997 John Wiley & Sons, Inc. Biotechnol Bioeng 56: 248-257, 1997.     

QSAR analyses on ginkgolides and their analogues using CoMFA, CoMSIA, and HQSAR

Ginkgolides, isolated from ginkgo balba leaves, were found to be powerful as natural antagonists of human platelet activating factor (PAF) in treatment of some diseases such as acute inflammation, tissue rejection, asthma, and ischemic injury. Ginkgolides have a cage skeleton consisting of six five-membered rings, therefore, are very tough to be synthesized. For finding new powerful substitutes of the natural ginkgolides for treating those diseases, three methods, viz. CoMFA, CoMSIA, and HQSAR, were used to investigate the relationship between 117 ginkgolide analogues with great structural diversity and their bioactivities against PAF receptor. The high q2 released from the different QSAR methods, ranging from 0.583 to 0.684, suggests that three rational and predictive QSAR models were successfully built. These models also show clearly how steric, electrostatic, hydrophobicity, and individual atom affect molecular bioactivity as antagonists of PAF. These results could also be used to account for the unusually higher bioactivity of ginkgolide B than other ginkgolides. The possible binding mechanism between ginkgolides and human PAF receptor was also deduced based on the QSAR models. Therefore, this study should be very helpful in discovering new drugs as PAF antagonists in fighting against various diseases related to PAF and PAF receptor.     

Ionization and self-association of unconjugated bilirubin, determined by rapid solvent partition from chloroform, with further studies of bilirubin solubility.

Our studies of equilibrium solubilization of crystals of unconjugated bilirubin (UCB) in buffered aqueous NaCl (1988. J. Lipid Res. 29: 335-348) suggested that the two carboxylic pKa values were 6.8 and 9.3 and the solubility of UCB diacid was 0.1 microM. These data, however, were not ideal, due to possible effects of crystal size, metastability, 96-h incubation times with formation of polar derivatives, impurities in the bilirubin, and imprecision of analyses at low concentrations of UCB ([UCB]). In the present study, designed to determine the pKa values and self-association of UCB, these problems were minimized by solvent partition of UCB from solution in CHCl3 into buffered aqueous NaCl. There was no crystal phase. Equilibrium was attained rapidly (10 min); UCB and CHCl3 were highly purified; and accurate diazo assay of low [UCB] in the aqueous phase, [Bw], was achieved by concentrating the UCB through back-extraction into a small volume of CHCl3. By determining effects on partition rations of varying the [UCB] in the CHCl3 phase, [Bc], we could assess also the self-association of UCB species in the aqueous phase. Partition ratios (P = Bw/Bc) did not differ between initial and repeat extractions, indicating insignificant concentrations of polar UCB derivatives. Similar P ratios were obtained when equilibrium was approached from a supersaturated aqueous phase. At 21-25 degrees C, mu = 0.15, the data (n = 76) fit the equation: log P = log Po + log[1 + 10(pH-A) + 10(2pH-B) + Bc.10(4pH-D)]; the bracketed terms reflect P for H2Bo (diacid), HB- (monoanion), B= (dianion), and (B=)2 dimer, respectively. Computer-fitted values for constants (+/- SD) were: Po = P for H2Bo = 5.79 x 10(-5); A = pK1 = 8.12 +/- 0.23; B = pK1 + pK2 = 16.56 +/- 0.10; pK2 = 8.44 +/- 0.33; D = pk22 + 2(pK1 + pK2) -log(2Po) = 37.64 +/- 0.07, and k22 = 0.26 microM-1 [formation constant of (B=)2 dimer]. In ancillary studies, multiple cycles of direct dissolution of UCB crystals revealed a progressive decrease in aqueous solubility of UCB as fine crystals were removed; this effect was minimal in CHCl3. Unlike in water, moreover, varied UCB crystal forms had similar solubilities in CHCl3, with [Bc] = 1.14 mM at saturation. As determined from [Bc]sat.Po, the aqueous solubility of H2Bo was 66 nM.(ABSTRACT TRUNCATED AT 400 WORDS)     

Conformational studies of antimetastatic laminin-1 derived peptides in different solvent systems, using solution NMR spectroscopy.

Due to its critical role in cancer progression, interactions between laminin-1 and the 67 kDa Laminin-Binding Protein (the 67 kDa LBP) have been the focus of a number of structural and biological studies. As laminin-1 is such a large and complex molecule, research interests have turned to the investigation of bioactive peptides derived from binding domains of laminin-1. Two peptides of interest, CDPGYIGSR (peptide 11) and YIGSR, both derived from the beta1 chain of laminin-1, have been shown to block invasion of basement membranes by tumor cells. Substituting the C-terminal arginine to lysine, a conservative substitution, results in a loss of peptide antimetastatic activity. This difference in bioactivity has been attributed, based on numerous modeling studies of free peptide conformations, to structural differences between YIGSR and YIGSK. Yet the nature of the 'active' free peptide backbone conformation has been a matter of debate and controversy. In order to test the validity of the structural modeling claims, we have undertaken detailed conformational studies of the two laminin-1 derived peptides YIGSR and CDPGYIGSR along with the biologically inactive YIGSK analog by two-dimensional solution 1H NMR spectroscopy in three different solvent systems. Herein we report that although both the active (YIGSR, CDPGYIGSR) and the inactive (YIGSK) peptides can adopt several closely related conformations in solution, the two peptides share similar conformational preferences, and there are no significant structural differences between the active and inactive peptides, contrary to previously reported modeling data. We conclude that the basis of the peptide biological activity, in contrast to published models, cannot be attributed to well-defined structural preferences of the free peptides. We infer that the difference in bioactivity observed between YIGSR and YIGSK originates primarily from the chemical nature of the arginine versus lysine sidechain substitution, rather than being due to a structural change in the free peptide conformations.