Minimal steric difference

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]... 

Because of the minimal steric difference between the substituents surrounding the alcohol moiety in simple 2-cyclohexenols, these are not easy to resolve by hydrolase-catalyzed reactions. However if a sterically bulky group can be temporarily introduced and then removed, such resolution will be facilitated. One example of this approach is the preparation of enantiomerically enriched 4-hydroxycyclohex-2-enone (64) (Scheme 4.25) [85]. A similar approach was used for the preparation of enantiomerically enriched cryptone (65) (Scheme 4.25) [86]. 

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]. 

MSDi is a descriptor of steric misfit defined as the number of unsuperposable nonhydrogen atoms for the maximal superimposition of the i th molecule to the reference molecule. MSD coincides with MTD when simple minimal steric differences are calculated with respect to the most active compound, no external atoms are considered in the hypermolecule, and the number of hypermolecule cavity vertices correspond to the atoms of the reference molecule. 

Ciubotariu, D., Deretey, E., Oprea, T.I., Sulea, T., Simon, Z., Kurunczi, L. and Chiriac, A. (1993). Multiconformational Minimal Steric Difference. Structure-Acetylcholinesterase Hydrolysis Rates Relations for Acetic Acid Esters. QuantStruct.-Act.Relat., 12,367-372. 

Fabian, W.M., Timofei, S. and Kurunczi, L. (1995). Comparative Molecular Field Analysis (CoMFA), Semiempirical (AMI) Molecular Orbital and Multiconformational Minimal Steric Difference (MTD) Calculations of Anthraquinone Dye Fiber Affinities. I.MoLStruct.(Theo-chem), 340, 73-81. 

Motoc, I., Holban, S., Vancea, R. and Simon, Z. (1977). Minimal Steric Difference Calculated as Nonoverlapping Volumes. Correlations with Enzymatic Hydrolyses of Ribonucleosides. Stadia Biophys., 66,75-78. 

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. 

Simon, Z. and Szabadai, Z. (1973). Minimal Steric Difference-Parameter and the Importance of Steric Fit for Quantitative Structure-Activity Correlations. Studia Biophys, 39,123-132. 

Simon, Z., Baiaban, A.T., Ciubotariu, D. and Balaban, T.-S. (1985a). QSAR for Carcinogenesis by Polycyclic Aromatic Hydrocarbons and Derivatives in Terms of Delocalization Energy, Minimal Sterical Differences and Topological Indices. Rev.Roum.Chim.,30,985-1000. 

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. 

In acid hydrolysis the ratio of the rate constants for the equatorial and axial conformers is found to be ke /kax 4.8, indicating that the steric effect of the equatorial conformation is smaller than that of the axial. Similar measurements of the con-formationally flexible unsubstituted cyclohexane carboxylate result in an averaged value that depends on the relative populations of the two conformations in the ground and transition states. The differential reactivity of optical isomers should exhibit a similar difficulty (but see the discussion on minimal steric difference, MSD). 

Ciubotariu, D., Gogonea, V. and Medeleanu, M. (2001) van der Waals molecular descriptors. Minimal steric difference, in QSPR/QSAR Studies by Molecular Descriptors (ed. M.V. Diudea), Nova Science, Huntington, NY, pp. 281-361. 

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. 

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. 

Simon, Z., Chiriac, A., Motoc, 1., Holban, S., Ciubotariu, D. and Szabadai, Z. (1976) Receptor site mapping. Search strategy of standard for correlations with minimal steric differences. Studia Biophys., 55, 217-226. 

MSD Minimal Steric Difference PEST Property Encoded Surface... 

The hyperstructure approaches MSD and MTD (minimal steric difference and minimal topological difference) and molecular shape analysis (MSA) are discussed in chapter 4.6, the use of similarity indices is discussed in chapter 9.4. 

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). 

Z. Simon, A. Chiriac, I. Motoc, S. Holban, D. Ciubotariu, and Z. Szabadai, Stud. Biophys., 55, 217 (1976). Receptor Site Mapping. Search Strategy of Standard for Correlations with Minimal Steric Differences. 

A. Chiriac, V. Chiriac, D. Ciubotariu, S. Holban, and Z. Simon, Eur. J. Med. Chem., 18,507 (1983). Minimal Steric Difference (MTD) Study for Flexible Molecules Substituted Acetic Acid Derivatives with Auxinic Activity. 

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