Steric parameters in QSAR

TIPKER VERLOOP STERIMOL MTD Steric Parameters in QSAR 281... 

Holecular refractivity, MR, was introduced as steric parameter in QSAR studies by the Pomona College group, instead, or... 

QSAR are useful In the design of pesticides and medicinal drugs, and In environmental problems such as the prediction of toxicity and blodegradablllty. An empirical relationship can be properly used only for Interpolation whereas one based solidly on well-established theory can be used at least to some extent for extrapolation as well. It seems of real Importance, then, to determine the nature and slgmiflcance of steric and bulk parameters In QSAR. 

STERIMOL and MTD (Minimum Topological Difference) steric parameters to account for steric influences in QSAR of pesticides have been described and applied in the literature. We have recently developed an improved version of the Simon MTD method, i.e. MTD parameters. The MTD and MTD methods will be described. The scope and limitations of the STERIMOL,... 

The results of the studies will be summarized. Details of the QSAR analyses are or will be published elsewhere, including intercorrelation matrices of the steric parameters mentioned. But relevant conclusions from e.g. intercorrelations will be dicussed. At this moment the STERIMOL method has been applied successfully in about 50 publications often with better results than other steric approaches, including MTD and MTD, especially in series with few substituent positions. A recent example is our study of DDT analogs. Brown et al. (9J analysed a series of 21 derivatives using the van de Waals (Vw) volumes as steric parameters. In Table I the equations are given in which the steric parameters are compared. 

The advent of molecular graphics and other facets of computational chemistry has led to an increased use of steric and electronic parameters in QSAR studies, and these quantities can now be calculated more precisely and... 

E, constants, as defined by eq. 51 (acid-catalyzed hydrolysis of RCOOR vs. CH3COOR ) [308], were the first parameters which have been used to describe steric effects in QSAR studies. 

Many other parameters related to size, c.g. van der Waals volumes, molar volumes, solvent-accessible surface, molar refractivity, etc. have been used to describe steric effects in QSAR equations. 

An important group of parameters in QSAR studies are terms derived from 2D and 3D structures of drugs, which are not directly related to lipophilic, electronic, or steric properties. 

Approach was used in deriving mechanistic information about odor intensity as well as insight into how this biological activity may be predicted. This paper will first briefly describe the history of QSAR, the QSAR parameters used, and how substituents for QSAR studies are selected. Several examples of the Hansch Approach used in taste and odor quality studies will next be presented. The balance of the paper will deal with the development of quantitative structure odor intensity relationships which will further expand upon the earlier study reported by this author (11). For example, the use of relatively new QSAR steric parameters in correlations with odor intensity data, and correlations of log P with literature odor intensity data determined on animal panels will be presented. This will be followed by conclusions derived from those studies, and areas of future work. 

The work described here consists of two types of approaches to the steric fit problem, The first approach consists of developing new parameters to describe different characteristics of the molecular shape Ci.e, branching, bulkiness) this is done by means of topological indices. The second approach is based on minimal steric differences, a measure for steric misfit which depends not only on molecular shape,but also on the receptor and allows a guess of the shape of the receptor cavity. Brief reviews will be given on other steric parameters which will often be compared, in QSAR s, with parameters developed by the authors of these Lecture Notes, Electronic parameters and hydrophobi-city-intermolecular force parameters, to be used together with steric parameters in OSAR s, are also briefly discussed. Other items include the metric introduced by minimal steric difference and computer programs developed in connection with our steric parameters. 

The fundamental assumption of SAR and QSAR (Structure-Activity Relationships and Quantitative Structure-Activity Relationships) is that the activity of a compound is related to its structural and/or physicochemical properties. In a classic article Corwin Hansch formulated Eq. (15) as a linear frcc-cncrgy related model for the biological activity (e.g.. toxicity) of a group of congeneric chemicals [37, in which the inverse of C, the concentration effect of the toxicant, is related to a hy-drophobidty term, FI, an electronic term, a (the Hammett substituent constant). Stcric terms can be added to this equation (typically Taft s steric parameter, E,). 

In this chapter, an attempt has been made to present a total number of 20 QSAR models (12 QSAR models for topo I inhibitors and eight QSAR models for topo II inhibitors) on 11 different heterocyclic compound series (an-thrapyrazoles, benzimidazoles, benzonaphthofurandiones, camptothecins, desoxypodophyllotoxins, isoaurostatins, naphthyridinones, phenanthridines, quinolines, quinolones, and terpenes) as well as on some miscellaneous heterocyclic compounds for their inhibition against topo I and II. They have been found to be well-correlated with a number of physicochemical and structural parameters. The conclusion, from the analysis of these 20 QSAR, has been drawn that the inhibition of topo I is largely dependent on the hydrophobicity of the compounds/substituents. On the other hand, steric parameters (molar refractivity, molar volume, and Verloop s sterimol parameters) are important for topo II inhibition. 

The character variables (i.e., the group volumes) are steric parameters of known utility in QSAR, but, despite the empirical success (i.e., eqs. 13 and 14), the steric meaning of locator variables is generally rather obscure. 

For years, we have been studying QSAR (quantitative structure-activity relationship) analyses of pesticides and other bioactive compounds. In many examples, we have found a decisive role of the steric effect in determining the activity variation. In this chapter, applications of various steric constants such as E E°, Vw and STERIMOL parameters to QSAR studies mostly from our own laboratory are reviewed. 

As exemplified above, various steric parameters can be properly utilized in QSAR studies depending upon the situation involved in the interaction between bioactive compounds and biomacromolecule. 

An effective QSAR parameter should correlate only to its specific property, be it electronics, lipophilicity, sterics, or something else, a- Values for R-groups in the meta and para positions have been found to account for only electronic effects. Substitution at the ortho position, however, is another story. Because ortho substituents are physically so close to the carboxylic acid, ortho R-groups affect the acid-base equilibrium through both electronic and steric effects. Therefore, the ortho tr-value (electronic parameter for QSAR studies. Despite their limitations, Hammett constants are by far the most commonly encountered electronic parameter in Hansch analysis. 

While the development of the Taft parameter is similar to that of Hammett and Hansch, / )-val ucs are based on rate constants instead of equilibrium constants. The Taft parameter is a measure of changes in activation energy, not standard free energy. Of the Hammett, Hansch, and Taft parameters, the Taft parameter is utilized the least in QSAR studies. Other steric parameters have been developed over time, and like the Taft parameter, all have shortcomings. One alternative steric parameter was developed by Marvin Charton of Pratt Institute in New York. Charton s parameter is based on the van der Waal radius of a substituent.6 Another alternative steric model is the STERIMOL parameter set developed by Arie Verloop of Philips-Duphar in Holland.7 Unlike Taft and Charton, Verloop... 

Based on the earlier work of Meyer and Overton, who showed that the narcotic effect of anesthetics was related to their oil/water partition coefficients, Hansch and his co-workers have demonstrated unequivocally the importance of hydrophobic parameters such as log P (where P is, usually, the octanol/water partition coefficient) in QSAR analysis.28 The so-called classical QSAR approach, pioneered by Hansch, involves stepwise multiple regression analysis (MRA) in the generation of activity correlations with structural descriptors, such as physicochemical parameters (log P, molar refractivity, etc.) or substituent constants such as ir, a, and Es (where these represent hydrophobic, electronic, and steric effects, respectively). The Hansch approach has been very successful in accurately predicting effects in many biological systems, some of which have been subsequently rationalized by inspection of the three-dimensional structures of receptor proteins.28 The use of log P (and its associated substituent parameter, tr) is very important in toxicity,29-32 as well as in other forms of bioactivity, because of the role of hydrophobicity in molecular transport across cell membranes and other biological barriers. 

The quantitation of steric effects is complex at best and challenging in all other situations, particularly at the molecular level. An added level of confusion comes into play when attempts are made to delineate size and shape. Nevertheless, sterics are of overwhelming importance in ligand-receptor interactions as well as in transport phenomena in cellular systems. The first steric parameter to be quantified and used in QSAR studies was Taft s constant (157). is defined as... 

Figure 10 Theoretical (a) and practical (b) representation of QSARs. Panel b describes a QSAR for the methanotrophic oxidation (activity of methane monooxygenase) of 6>r /i6>(Ci2)-substituted biphenyls. The structural backbone was biphenyl, and the substituents considered included all halogens, methyl-, methoxy-, hydroxyl-, nitro-, and amino-moieties (Lindner et al, 2003). The molecular descriptors used in (b) are (charge on the ortho-csubon), (Taft s steric parameter), and log ow...

Muresan, S., Bologa, C, Mracec, M., Chiriac, A., Jastorft B., Simon, Z. and Naray-Szabo, G. (1995). Comparative QSAR Study with Electronic and Steric Parameters for cAMP Derivatives with Large Substituents in Position 2, Position 6 and Position 8.1.MolStruct(Theochem), 342,161-171. 

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