Verloop parameters

The substitution pattern of the 4-aromatic residue is also important for the activity, the ortho-substitution being the best one in terms of potency and selectivity. A Hansch analysis on a series of ortho-derivatives has shown a significant correlation between calcium antagonist activity and steric hindrance of the substituent, while no relationship was found for either electronic or lipophilic parameters [3]. The best SAR correlation was obtained when the B1 steric parameter (the Verloop parameter) was introduced into the analysis [4]. The calcium channel-blocking activity increases as B1 increases, which probably indicates that steric hindrance in the ortho-position is required to fix the dihydropyridine structure into a favorable conformation in which the aromatic group is approximately perpendicular to the dihydropyridine ring (Fig. 7.12). 

Sterimol parameters ( Verloop Sterimol parameters Verloop parameters)... 

Verloop parameters Sterimol parameters Verloop Sterimol parameters Sterimol parameters vertex adjacency matrix adjacency matrix vertex centric indices - centric indices vertex chromatic decomposition chromatic decomposition... 

As steric parameters, values and van der Waals radii have frequently been used. More appropriate are the so-called Verloop parameters L and B, which describe the length and different widths of substituents. " Molecular connectivity indices x belong to a large group of different topological parameters. ... 

Taft sterlc parameter Verloop sterlmol constants ... 

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. 

J. L. Fauchere, M. Charton, L. B. Kier, A. Verloop, V. Pliska, Amino Acid Side Chain Parameters for Correlation Studies in Biology and Pharmacology , hit. J. Pept. Protein Res. 1988, 32, 269 - 278. 

MR, the molar refractivity, which parameterizes polarizability and steric effects and Verloop s parameters, which are steric substituent values calculated from bond angles and distances. 

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

Another classical measure of the molecular geometry of substituents is the Verloop steric parameter. This is calculated from bond angles and atomic dimensions— primarily the lengths of substituent groups and several measures of their width. Trivial as this may sound, the consideration of molecular bulk is an important and often neglected factor in making multiple quantitative correlations of structure and pharmacological activity. Balaban et al. (1980) devised several related methods that are still in use today. 

Many QSAR applications of the MSD and MTD parameters have been published Simon and collaborators (one should consult the review articles 16 e)), Duvaz et al. 25a), Carles and Goursot26), Verloop 25b). 

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. 

Although these parameters represent the shape of substituents as a set, there is some collinearity among Bx, B2 and B3 for a number of substituents. Thus, Bx, B4 and L, as the most independent variables, are usually used in QSAR analysis 33). More recently, Verloop proposed the maximum width parameter, B5, and showed that, in most cases, B5 works well in place of B4 35). Since they are defined mechanically as the length or width, the background of their utilization along with other free-energy related parameters is not necessarily clear. 

Verloop, A. et al. Applications of STERIMOL Parameters to Drug Design, in Steric Effects in Drug Design (eds. Motoc, I., Charton, M.) Springer, Berlin, Heidelberg, New York, 1983, p. 137... 

Bioisosteric replacement can be made from a position of knowledge, if the desirable properties of the substituent or substructure to be changed have been characterized. Such properties can include (with typical parameters) (a) size (volume, molar refractivity, surface area, Taft s) (b) shape (Verloop length and breadth, bond angles, interatom distances) (c) lipophilicity (log P, tt,/) (d) solubility (log S) (e) ionization state (pKg, a) ... 

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... 

Verloop, A., Tipker, J. Use of Linear Free Energy Related and Other Parameters in the Study of Fungicidal Selectivity. Pest. Sci. 1976, 7, 379-390. 

These can be broadly divided into those that apply to sections of the molecule and those that involve the whole molecule. The former include parameters such as van der Waals radii, Charton s steric constants and the Verloop steric parameters. The latter range from relative molecular mass (RMM) and molar volumes to surface area. They have all been used to correlate biological activity to structure with varying degrees of success. 

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