Cynthia Dias Selassie

QSAR: then and now.

In this review, the evolution of QSAR is traced from the insightful observations of Crum-Brown and Frazier to Hammetts critical equations and finally Hanschs seminal contributions on hydrophobicity and modelling of biological activity based on extrathermodynamic principles. Todays QSAR models can stand alone, augment other graphical approaches or be examined in tandem with equations of a similar mechanistic genre to truly reveal the power of the paradigm. This review will focus on the three standard classifications routinely used in QSAR analysis electronic, hydrophobic, and steric, as well as topological indices. Electronic parameters will focus on Hammett sigma constants and their numerous variations. Dipole moments, hydrogen bond descriptors and quantum chemical indices as well as applications of their utilization will be described. The hydrophobicity parameter will be examined by tracing its early history, its operational definition and its determination by either experimental methods or computational calculations. Steric parameters, which run the gamut from size to shape, will be described by Tafts, Hancocks, Chartons, Fujitas, Verloops and Simons contributions. Topological effects, delineated by connectivity indices, kappa shape and electrotopological indices of Kier and Hall are also described. Examples of QSAR models incorporating most of these parameters are reviewed. In cases where the 95% confidence intervals of variables are available, they are listed in parentheses. A brief Comparative QSAR analysis of non-nucleoside reverse transcriptase inhibitors (NNRTIs) is outlined and various models obtained by different groups examining 4, 5, 6, 7-tetrahydro-5-methylimidazo [4, 5,1-j,k][1,4] benzodiazepin-2(1H)-ones (TIBO) and 1-[(2-hydroxyethoxy)methyl]-6-(phenylthio)-thymine (HEPT) derivatives are compared for mechanistic insight that could be useful in the process of inhibitor design.

Phenol toxicity in leukemia cells: a radical process?

The multiple functions of the phenol moiety that are widely present in disparate sources such as drugs, pesticides, teas, fuel additives and surfactants have not been clearly delineated. The differences in behavior of phenols, which run the gamut from aberrations in DNA/chromosomes to suppression of genotoxic activity of carcinogenic compounds, merit further attention. In this study, a through examination of the growth inhibition patterns of 37, simple 3- and 4-substituted phenols in mouse leukemia cells was carried out and the following quantitative structure-activity relationship (QSAR) was obtained for the 23 electron releasing substituents in X-phenols: log 1/IC50 = -1.58 sigma(+) +0.21 log P + 3.10. In this QSAR, IC50 is the concentration of phenol that induces 50% inhibition of growth. P is a measure of the hydrophobicity of each phenol and Browns electronic parameter, sigma+, represents the electronic effect of the substituent. The negative dependence on sigma+ is strongly reminiscent of what is observed in the developmental toxicity of phenols on rat embryos as well as for the radical abstraction of a hydrogen atom from phenolic groups. The other 15 electron-attracting substituted X-phenols clearly show a linear dependence on hydrophobicity alone: Log 1/IC50 = 0.62 log P + 2.35. The bifurcation in mechanism of action of this large set of diverse phenols is novel and unusual. It suggests that two distinct processes are operative. In the case of electron releasing substituted phenols, the observations are not inconsistent with a radical mediated process while with electron attracting substituted phenols, non-specific toxicity as modulated by hydrophobicity, appears to predominate.

The use of crystallography, graphics, and quantitative structure-activity relationships in the analysis of the papain hydrolysis of X-phenyl hippurates

Abstract The effect of 3- and 4-monosubstitution and 3,5-disubstitution on the phenyl leaving group of the papain-catalyzed hydrolysis of 27 phenyl hippurates is reported. The Michaelis-Menten constant ( K m ) at 25.0 °C and pH 6.0 was determined for the substrates and, in addition, the first-order rate constant ( k ) for the uncatalyzed hydrolysis under the same conditions was measured. A quantitative structure-activity relationship was derived from the K m values. The conclusions from this analysis are in excellent agreement with the binding mode of the hippurates as shown by a molecular graphics analysis of the binding cavity which has been defined by X-ray crystallography.

Toxicology of benzyl alcohols: a QSAR analysis

There is an evidence that benzyl alcohols may exhibit toxicity via a radical mechanism. To test this possibility, we studied the toxicity of para substituted benzyl alcohols on rapidly dividing cancer cells (L1210 leukemia). This system has previously found utility in studying the apparent radical toxicity of a variety of phenols. However, no evidence could be found for an electronic effect and the cellular toxicity was associated primarily with hydrophobicity. Comparison of this quantitative structure-activity relationships (QSAR) with others for the reactions of benzyl alcohols in diverse systems provides insight into mechanisms of action. A QSAR for the interaction of benzyl alcohols with protozoa yields an equation that is dependent on both hydrophobicity and acidity of the OH group versus a mixture of bacteria and fungi, the critical dependence on hydrophobicity prevails with a small dependence on a resonance-stabilized, radical mediated electronic effect. The chloramphenicols provide an instructive example, where the radical mediated electronic effect overshadows the hydrophobic contribution to bacterial toxicity. These various QSAR for benzyl alcohols indicate that mechanisms of growth inhibition in vitro vary depending on cell/organism type, the strength of the bond and lability of the hydrogen, and the strength of the initiating radical reagent.

Mechanism-based QSAR approach to the study of the toxicity of endocrine active substances*

Mechanism-based QSAR models for interactions between various ligands and the estrogenic receptor are developed by using well-developed physicochemical parameters. Common features of these QSARs are identified, and deficiencies in some datasets are highlighted. The relative binding affinities of various substituted hexestrols to estrogen receptors are examined in terms of their steric, electronic, and hydrophobic attributes. Different QSARs for hexestrols and tamoxifens reveal that steric effects are of overriding importance in variations of binding affinity. In the few cases where a large number of diverse substituents are located on aromatic rings, electronic effects emerge and suggest that electron-donating groups enhance binding to the receptor while hydrophobicity plays a marginal role in decreasing binding affinity. With substituted phenols bearing alkyl-type substituents and substituted hydroxy-biphenyls, the binding is strictly dependent on hydrophobicity and size. These QSAR models are described in detail and examined together to illustrate the utility of lateral validation in mechanistic interpretation.

Comparison of quantitative structure-activity relationships of the inhibition of leukemia cells in culture with the inhibition of dihydrofolate reductase from leukemia cells and other cell types.

A set of 2,4-diamino-5-(3-X-phenyl)-s-triazines was used to inhibit the growth of tumor cells (L5178 leukemia) in culture. The molar concentration (C) of triazine causing 50% reduction in the rate of cell growth was used to develop a quantitative structure-activity relationship: log 1/C = 1.32 pi - 1.70 log (beta.10 pi + 1) + 0.44I + 8.10, where pi is the hydrophobic constant for X, beta is a disposable parameter, and I is an indicator variable for congeners containing a -CH2Z-C6H4-Y moiety (Z = O or NH). This equation is compared with similar equations derived for the inhibition of dihydrofolate reductase from leukemia cells and bovine liver.

QSAR for the cytotoxicity of 2-alkyl or 2,6-dialkyl, 4-X-phenols: the nature of the radical reaction

In a continuation of studies on the radical mediated toxicity of phenols to leukemia cells, a set of di- and tri- substituted phenols with mostly alkyl substituents in the ortho position were examined. These analogs are similar in structure to the commercial antioxidants BHA and BHT. A QSAR analysis of their growth inhibitory constants led to the formulation of this simple but unusual equation based on 18 congeners:ES-2 is the Taft steric parameter for the larger of the two ortho substituents while ER is Otsus radical parameter, which was originally defined to correlate radical reactions.

Separation of electronic and hydrophobic effects for the papain hydrolysis of substituted N-benzoylglycine esters

The role of hydrophobic and electronic effects on the kinetic constants kcat and Km for the papain hydrolysis of a series of 22 substituted N-benzoylglycine pyridyl esters was investigated. The series studied comprises a wide variety of substituents on the N-benzoyl ring, with about a 300,000-fold range in their hydrophobicities, and 2.1-fold range in their electronic Hammet constants (sigma). It was found that the variation in the log kcat and log 1/Km constants could be explained by the following quantitative-structure activity relationships (QSAR): log 1/Km = 0.40 pi 4 + 4.40 and log 1/kcat = 0.45 sigma + 0.18. The substituent constant, pi 4, is the hydrophobic parameter for the 4-N-benzoyl substituents. QSAR analysis of two smaller sets of glycine phenyl and methyl esters produced similar results. A clear separation of the substituent effects indicates that in the case of these particular esters, acylation appears to be the rate limiting catalytic step.

Trypsin hydrolysis of X-phenyl hippurates

The kinetics of hydrolysis of eight substituted phenyl hippurates by trypsin at pH values 6, 7 and 8 were investigated and the kinetic constants Km, kcat (kcatalysis) and kcat/Km were shown to fit the Hammett equation. The rho (rho) value obtained from the correlation of trypsin binding with this class of esters was compared with that obtained with other serine and cysteine proteases. The rho value for trypsin was similar to that obtained for alpha-chymotrypsin in that both enzymes reveal a pronounced dependence on through resonance (sigma-) in the formation of the Michaelis complex and the acyl-enzyme. It is apparent that through resonance facilitates the leaving of the phenoxy moiety during catalysis in the serine proteases but not in the case of the cysteine or bacterial serine proteases.

Chapter 7:Modeling Chemical Structure-Log P

Log P, a measure of molecular hydrophobicity, is one of the most significant descriptors in the field of QSAR analysis and rational drug design. It wields an important role in ADMET phenomena and serves as a key predictor of the environmental fate of most chemicals. Log P values can be measured experimentally or predicted from molecular structure. In this chapter, a synopsis of various experimental approaches for the measurement of log P values that run the gamut from the highly reliable and traditional shake-flask method to automated and rapid methodologies is provided. Computational methods that are utilized for rapid and generally accurate log P calculations are also discussed. Since log D (apparent log P) is related to log P via the ionization constant (pKa), common methods for the prediction of pKa values are included. Numerous software programs are now available for the calculation of log P and pKa values and some commonly used ones are listed. Various applications of log P are exemplified by their use in the delineation of various QSAR models pertaining to absorption, metabolism and toxicity phenomena.