STERIMOL usefulness

The Kd(X) values thus obtained (Table 3) were analyzed by the multivariant technique using such parameters as n, a0, Bt, Ibmch, and Ihb, where Bj is a STERIMOL parameter showing the minimum width of substituents from an axis connecting the a-atom of the substituents and the rest of molecule, and Ibrnch, an indicator variable representing the number of branches in a substituent. 

Use of STERIMOL, MTD, and MTD Steric Parameters in Quantitative Structure-Activity Relationships... 

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. 

Another example of the use of the MTD and MTD approaches can be found in a series of optically active o-phenoxypropionic acids with auxin-like activity, partly published in ( ). The R-stereo isomers are much more active than the S-analoges. Both series were analyzed by Lien et al. (10) and a correlation with ir, a and the Van der Waals volume was found. The Pfeiffer rule is explained in terms of different structural requirements for the substituents as measured by and van der Waals volume. Analysing the series using STERIMOL delivered equations containing too many parameters. In Table III the equations are given as a result of... 

When less substituent positions are present STERIMOL can be used but in those cases there is often hardly any difference in results if compared with the MTD method. This is illustrated by our version of the QSAR of the insecticidal activity against American cockroaches of 36 substituted benzyl chrysanthemates. 

At this point it was clear that the highest potential for increased activity was by substitution in the 2-position of the biphenyl alcohol. We prepared the sequence of compounds shown in Table 1. Substituents were again chosen to maximize the parameter space covered within the relatively stringent synthetic limitations of the biphenyl substitution pattern. The application of regression analysis to the data for these compounds provided no clear relationship between structure and activity when the parameters in our standard data base were used. The best linear fit was found for B4, the STERIMOL maximum radius. However, the correlation coefficient was only 0.625. 

In the following years, various steric parameters have been applied to the analysis besides the Taft Es value. For instance, the Hancock corrected steric E , the Bondi molecular volume Vw, and the Verloop STERIMOL parameters have been used to rationalize various steric effects depending upon the interactions involved. At every addition of such parameters, the versatility of the approach has been expanded remarkably. The number of successful applications has been growing enormously leading to the present state of development. 

After separating steric effect by the STERIMOL term, the slope of the ct° terms in Eq. 40 and 41 is close to those observed for the same type of acylation reactions in a number of physical organic systems37>. Thus, STERIMOL values can well be used as free-energy-related parameters in combination with ct and parameters and provide informations about three-dimensional aspects of the interactions between drugs and biomolecules. 

Irrmost correlations in this review, the steric parameters are supposed to be best among others. In deriving Eq. 43 for N-phenyl tetrahydrophthalimide herbicides, STERIMOL parameters are the best ones 42). In Eq. 53 for lindane analogs, Vw works much better than MR 70). However, this does not necessarily mean that the correlations mentioned here are always finalized. Further improvement may be possible using other steric parameters. 

Several shape descriptors are defined within more general approaches to - molecular descriptors. This is the case of - Kier shape descriptors, -> shape profiles, -> shadow indices, -> WHIM shape descriptors, - Sterimol shape parameters L/Bj and B1/B5, molecular - periphery codes, and -> centric indices. Other approaches to the study of molecular surface and shape are Mezey 3D shape analysis and Hopfinger - molecular shape analysis. -> Triangular descriptors have also been used to characterize molecular shape to search for similarities among molecules. 

Diflubenzuron and its analogues aroused the interest of researchers engaged in quantitative structure-activity relationship (QSAR) studies. Thus, Verloop and Tipker (1977 1978) demonstrated on a number of diflubenzuron analogues the feasibility of STERIMOL parameters in QSAR analyses, permitting a refined insight into the shape of the substituents. Bordas et al. (1979) carried out a retrospective study of activity data on diflubenzuron derivatives, by using Free-Wilson analysis, factor analysis and principal component analysis. The factors extracted by principal component analysis and factor analysis were used as... 

Geometrical parameters, such as molecular shape parameters," sterimol descriptors, volume, bulk parameters, " " and 3D Wiener index,"" have been developed and used in SARs. Such parameters are derived from the relative distances of atoms in the 3D Euclidean space. We give below some examples of QSARs using 3D descriptors. 

As a way to solve both of these problems in using Es to correlate biological properties, Verloop and co-workers expanded the approach of using the 3D structure of the substituent. This is implemented in the STERIMOL computer program. They originally calculated five characteristic steric properties of a substituent from the van der Waals surface of the molecules. For this they used the atomic and bond properties that are used to construct the CPK physical models that were popular at the time. Later they decided that three descriptors were sufficient ... 

It Is Interesting that In the Individual substituent positions molar volume (MR) was found to be the relevant parameter rather than ff. Eg or the STERIMOL descriptors. This fact and the positive coefficients for MR suggest that the enzyme-Inhibitor Interaction proceeds via London dispersion forces (31, ) and the binding to the enzyme Is favored If the bulky substituents are In meta or para positions, which Is In accordance with the earlier results (11). The parameter H-DO In position I seems to be Important In the regression. It systematically appears In each equation. Its path coefficient and partial r value, however. Is relatively low compared to those of Jit and MRjjj. In addition, the H-DOj variable Is not very useful because these Indicator parameters are the most poorly defined and the number of proton donor substituents (H-DO-1) Is rather small. 

The compounds were synthesized according to known methods. The Sterimol parameters by Verloop et al. (16.17) proved very useful in the QSAR work. CNDO/2 calculations were carried out by using a QCPE program ( ) which was modified inhouse. studies were made in... 

Sigma-rho corrections were assigned equally to the substituents at positions 6 and 7. Revised STERIMOL (L, B1 and B5) parameters were calculated following established methods.f27.28l The data matrices consist of lipophilicity (F), molar refractivity (MR), STERIMOL (L, Bl, B5) parameters and de novo indicator variables for substituents in positions 1, 6 and 7. The contribution to the partition coefficient by the substituents at positions 6 and 7 were summed, 2F(6,7), as were the molar refractivity contributions, 2MR(6,7). These two sets of summed variables paralleled a similar approach used by Koga in his QSAR analysis of a set of quinoline derivatives. (231 At the same time, the limitations that apply to summed n values, particularly where there is a significant a-p interaction were kept in mind.f22.29.301 The latter is represented as API in the data tables and its significance was evaluated in some of the regression models. In order to check for parabolic relationships, squared terms for the partition coefficient, molar refraction, and STERIMOL parameters were evaluated. 

Due to some criticism [50] and due to a number of chance correlations in the QSAR literature, arising from uncritical combinations of linear and squared terms i.e. 10 possible values for one site of substitution and many more for several different sites), Verloop reduced the width parameters to Bj, being the smallest width, and B5, now being the largest width orthogonal to L, but independent of the angle between B, and B5 (Figure 8) [336, 343]. The use of the STERIMOL parameters in QSAR studies has been reviewed [287, 335, 336, 343]. 

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