Cellular injuries and storage stability of spray-dried Lactobacillus rhamnosus GG

The characterization of chemical structures using molecular properties. A survey

Parameter values for 59 common substituents and 74 descriptors used in QSAR studies were compiled. This data matrix was analysed by a variety of multivariate techniques. Linear regression confirmed that lipophilicity can be factorized into two terms, one related to molecular bulk and the other to polarity. Principal component analysis (PCA) of parameters revealed 5 significant principal components and a grouping of lipophilic, steric and electronic parameters. The different loadings of parameters with 5 PCA were also explored. The classification of substituents by cluster analysis (CA) proved rather disappointing. In contrast, the SIMCA method classified substituents of increasing bulk into 5 groups of increasing polarity.

Pattern recognition study of QSAR substituent descriptors.

Publisher Summary This chapter provides an introduction to some of the pattern recognition techniques and illustrates examples of their use in the investigation of quantitative structure–activity relationships (QSAR). Pattern recognition methods have much to offer the drug designer, particularly as the calculation and collation of data, both biological and physicochemical, becomes easier with the widespread use of computer databases, molecular modeling systems, and property prediction packages. Some of the techniques, however, suffer from difficulties in interpretation and the dangers of chance effects have received little attention. The wider use and understanding of these methods is expected to enhance their utility in drug design. These methods are being applied increasingly in other areas of pharmaceutical research, such as in the analysis of clinical data, and new techniques for analysis should continued to be developed and applied in this field.

[30] Pattern recognition methods in rational drug design

Empirical correlations between gas-chromatographic retention data and physical or topological properties of solute molecules

Values of the substituent entropy constants σso for monosubstituted methane and benzene derivatives were determined from the standard entropy of the 3rd law of thermodynamics. This parameter is orthogonal to σt or σπ, and seems preferable to π, Es, MR, Mw, Pr and Vw. Two examples of QSAR are successfully analysed in terms of σso.

Utility of the substituent entropy constants .SIGMA.s.DEG. in the studies of quantitative structure-activity relationships.

The novel substituent entropy constant σs° represents the molecular connectivity X, one of the QSAR descriptors developed by molecular topology. It is closely correlated with chromatographic retention data, such as retention time Rt or RT, and with retention index R.I. and specific retention volume Vg. Also, water solubility, boiling point and partition coefficient are represented by σs°.

Novel substituent entropy constant .SIGMA.s0 represents the molecular connectivity x and it related indices.

Eighteen kinds of current QSAR parameters were analysed by the cluster analysis, and divided into 4 groups, namely, cluster 1=σi, |σi|, σm, F ; cluster 2=σπ, σp, R ; cluster 3=MR, Pr, Vw, σs°, △S°, π, Es, Mw ; cluster 4=|σπ|, ι, μ. Of the eight kinds of parameters belonging to cluster 3, MR, Pr, and Vw can be substituted by σs°, whereas π (aromatic group) and Es are expressed by the linear combination of σi, σπ and σs°.

Characterization of novel substituent entropy constant by cluster analysis

Biological response (BR) can be expressed by the equation BR=α (σso)2+bσso+cσi+dσx+e for quantitative structure-activity relationships (QSAR) analyses. The values of σi and σx originally take+or-sign depending on the electronic character of the substituent group and can be used to describe strong drug-site interactions. On the contrary, original chemical significance is lost in |σi| and |σx|, which can be applied to weak drug-site interaction, where dipole-dipole or dispersion interaction could be predominant. The coefficient c of the BR equation becomes the same in meta- and para-substituted benzene series. When σx is real, σx/m+σx/p gives a better result than σx/m, p, while on the other hand, when σx is absolute, |σx|/m, p gives a good result. As regards the entropy term a (σso)2+bσso, the ortho-substituted benzene series requires the+sign for a and the-for b, whereas for meta-and para-substituted series, this is reversed. When the relative weight of the entropy term decreases and the contribution of the enthalpy term becomes predominant, the quantum chemical index could often be used as an effective scale for BR.

Studies on Quantitative Structure-Activity Relationships. IV. Usefulness of the Novel Substituent Entropy Constant σso and the Sign of the Enthalpy Parameter

QSAR analysis of dihydrofolate reductase inhibition by Baker triazines - 4, 6-diamino-1, 2-dihydro-2, 2-dimethyl-(x-substitutedphenyl)-s-triazines - was achieved for 21 congeners by the linear combination of the four kinds of parameters (σs°)2, σs°, σi and σπ· The successful result is expressed by the equation, log (1/C) =-25.29 (±7.58) (σs°)22+7.04 (±2.64) σs°3, 4+3.22 (±1.68) |σi|3, 4+3.68 (±3.22) |σπ| +6.37 r=0.981, SE=0.09, F=103.7 Subscripts 2, 3 and 4 denote the positions of the x substituents. This suggests that a four parameter analysis of this type is the most promising in QSAR analyses.

Akihiro Iwata

Papers

Utility of the substituent entropy constants .SIGMA.s.DEG. in the studies of quantitative structure-activity relationships.

Novel substituent entropy constant .SIGMA.s0 represents the molecular connectivity x and it related indices.

Characterization of novel substituent entropy constant by cluster analysis

Studies on Quantitative Structure-Activity Relationships. IV. Usefulness of the Novel Substituent Entropy Constant σso and the Sign of the Enthalpy Parameter

The substituent entropy constant .SIGMA.X(X=S0) used in the QSAR investigation of dihydrofolate reductase inhibition by Baker triazines.