The application of computational techniques to medicinal chemistry is growing at a tremendous rate. Quantitative structure-activity relationships (QSAR), which relate biological and toxicological activities to structural features, have been employed widely to correlate structure to activity. A difficulty of this approach has been nonuniformity of parameter sets and the inability to examine contributions across properties and data sets. Linear solvation energy relationships (LSER) developed by Kamlet and Taft circumvent many of the difficulties and successfully utilize a single set of parameters for a wide range of physical, chemical, and biological properties. We have replaced the LSER solvato-chromatic parameters with theoretically determined parameters to permit better a priori prediction of properties. Comparison of the two parameter sets for five biological activities is presented, showing the excellent fit of the theoretically determined parameters.

The application of computational techniques to biology, chemistry and physics is growing rapidly. Quantitative structure–activity relationships (QSAR) have been used widely to relate biological activities and physicochemical properties to molecular structural features. A difficulty in this approach has been non‐uniformity of parameter sets resulting in the inability to examine contributions across properties and data sets. Linear solvation energy relationships (LSER) developed by Kamlet and Taft successfully utilize a single set of parameters to correlate a wide range of biological, chemical and physical properties. The empirical LSER solvatochromic parameters have been replaced with theoretically determined parameters to permit greater ease in a priori property prediction. These TLSER descriptors have given good correlations and interpretations for some biological activities. This paper discusses the application of these descriptors to six physicochemical properties involving equilibria, kinetics and spectra. The results show good correlation and physical interpretation.

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A computational investigation of the conformational preferences of 2-phenethylamine has been carried out with a variety of techniques. To determine the intrinsic (in the absence of a solvent medium) conformational preferences of the 2-phenethylamine system, ab initio calculations at various levels of theory up to the MP2/6-311+G(d,p)//MP2/6-31G(d,p) level were carried out. This is the most sophisticated level of theory that has been applied to this biologically important system to date. In the absence of a solvent medium, phenethylamines prefer a folded gauche conformation for both the charged and neutral amines, indicating a favorable interaction between the amino group and the aromatic ring. To probe the nature of this intramolecular interaction further the effects of ring substituents on the conformational preferences were studied. The results have been compared to those obtained with semiempirical and molecular mechanics force field methods. The molecular mechanics force fields employing default parameters typically performed poorly for this system, but the results were improved significantly if the electrostatic charges were replaced. The effects of aqueous solvation have also been investigated with the GB/SA and the SM2 continuum solvation models. The best agreement with experiment is obtained when the MP2/6-311+G-(d,p)//MP2/6-31G(d,p) results are combined with the SM2-calculated solvent effect. Results of nearly the same quality can be obtained if the solvent effect is calculated with the GB/SA solvation model using AM1-CM1A charges.

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