Minimal steric difference method

Other approaches to expressing topological differences include treating the problem of directionality of steric effects by the direct expedient of modeling a substituent and calculating its extension in five orthogonal directions (e.g., the minimal steric difference method, [289]). Other approaches [111-115,290-295]... 

Simon, Z., Dragomir, N., Plauchitiu, M.G., Holban, S., Glatt, H. and Kerek, F. (1973). Receptor Site Mapping for Cardiotoxic Aglicones by the Minimal Steric Difference Method. EurJ.Med. Chem., 15,521-527. 

Popoviciu, V., Holban, S., Badilescu, 1.1. and Simon, Z. (1978) Steric mapping of estrogenic receptor sites by a minimal steric difference method. Studia Biophys., 69, 75-76. 

The three versions of the minimal steric difference method for evaluation of steric effects are described in Chapters 4,5 and 6. Topological indices derived in the framework of chemical graph theory are discussed in Chapter 3, Good results obtained in the study of octane numbers for alkanes justify the attentive investigation of the possibilities of topological indices for QSAR-studies, Up to now, only the Randici index was studied in this respect (see refs, quoted in Chap.3),... 

The Minimal Steric Difference MSD) method is the first version of the MTD QSAR approach, where each molecule is compared with the molecule with the highest biological acitivity in the data set, taken as the -> reference structure instead of the hypermolecule. The assumption is that the most active molecule fits into the binding site best [Simon and Szabadai, 1973]. 

Oprea, T.I., Ciubotariu, D., Sulea, T. and Simon, Z. (1993). Comparison of the Minimal Steric Difference (MTD) and Comparative Molecular Field Analysis (CoMFA) Methods for Analysis of Binding of Steroids to Carrier Proteins. Quant.Struct.-Act.Relat., 12,21-26. 

The minimal steric difference (MSD) is another example of a specifically designed steric constant (105) in which the parameters are defined as the non-overlapping volume of a certain molecule with a standard molecule possessing the biological activity under study. The reference molecule is usually the natural substrate, which often must be arbitrarily chosen. For conforma-tionally flexible molecules the minimum energy conformations are chosen. This eliminates considerations of other conformers that may be important. Further, this method does not take into consideration that the steric interaction may cause a conformational change in the molecule or cause a change in its reactivity. 

Oprea TI, Ciubotariu D, Sulea T, Simon Z. Comparison of the minimal steric difference (MTD) and comparative molecular field analysis (CoMFA) methods for analysis of binding of steroids to carrier proteins. Quant Struct-Act Relat 1993 12 21-26. 

The importance of molecular stereochemistry for biological activity was recognized 100 years ago, by Emil Fisher, with his lock and key theory for enzymatic reactions (Motoc 1983). The steric fit of dmg molecule (L-ligand) with its target (usually, receptor, R) depends upon both the shape of the biological receptor and the shape of ligand molecule. MTD (minimal topological difference) method takes into... 

The Monte Carlo version of minimal steric difference (denoted as MCD) improves the computation of non-overlapping volumes in the standard-ligand superposition, translating thus the topological MSD parameter into the (3D) metric context (Mojoc et al. 1975 Ciubotariu et al. 1983). In order to calculate the MCD, the molecules are described by the Cartesian coordinates and vdW radii of their atoms. The atomic coordinates implicitly specify the way one achieves the superposition all molecules of the series are represented in the same Cartesian coordinate system. The mathematical method used in the MCD-technique for computation of nonoverlapping volumes is the Monte Carlo method (Demidovich and Maron 1987). 

FIGURE2.21 Generic worldofthequantitativestrocture-activity/property relationships-QSA(P)R - through classical, 3D, decisional and orthogonal methods of multivariate analysis of the chemical-biological interactions. In scheme, MSD-MTD, CoMFA, and PCA stand for the minimal steric difference-minimal topological difference , comparative molecular field analysis and principal component analysis , respectively after (Putz Lacrama, 2007). 

Ninimal steric difference", NSD, depends both on the shape of the effector molecule and of the biological receptor. The basic idea of the minimal steric difference concept is that the affinity of effectors for a receptor is a linearly decreasing function of the sum of nonoverlappable volumes of effector molecule and receptor cavity. In order to have this concept at work, one must have a guess for the shape of the receptor cavity and a simple method to evaluate the nonoverlappable volumes - which is the MSD. Thus, if A. is the biological... 

Simon and his coworkers have developed (426) a quantitative 3D-QSAR approach, the minimal steric (topologic) difference (MTD) approach. Oprea et al. (452) compared MTD and CoMFA on affinity of steroids for their binding proteins and found similar results. Snyder and colleagues (453) developed an automated method for pharmacophore extraction that can provide a clear-cut distinction between agonist and antagonist pharmacophores. Klopman (404,454) developed a procedure for the automatic detection of common molecular structural features present in a training set of compounds. This has been used to produce candidate pharmacophores for a set of antiulcer compounds (404). Extensions (454)of this approach allow differentiation between substructures responsible for activity and those that modulate the activity. 

Methods for evaluating the steric misfit are minimal topological difference and -+ molecular shape analysis. 

Since the above minimization methods can get stuck in shallow local minima, the resulting structures do not necessarily correspond to any stable conformation of the molecule. Minimization of an MM energy function means that all substantial steric overlaps are resolved, and that all bond lengths and bond angles are adjusted to near equilibrium values. Therefore, local minimization is frequently used for the refinement of conformations obtained by other search methods. In the case of a low-dimensional search space, a number of, but not necessarily all, local minima can be located by repeated local minimization from different, e.g., random, starting points (.see Section 2.5.1). 

Matsui et al.82) have analyzed the same data of log l/Kd(X) for cyclodextrin-phenol systems from a somewhat different standpoint. They computed the minimal van der Waals interaction energies (Emin) for the systems by using the same method as described in a previous section (Table 4). The calculated Emin values were applied, in place of such steric parameters as Ibrnch and B1( to the correlation analysis. The correlations obtained are given in Eqs. 24 to 27. 

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