Theoretical approaches to pharmacology
Joyce J. Kaufman · International Journal of Quantum Chemistry · 2009
The major various factors that enter into a theoretical consideration of pharmacological “structure–activity” relationships are (1) topological, topographical, and substructure analyses and related properties of the drugs (and related biomolecules); (2) electronic structure of the drugs (and related biomolecules); (3) physicochemical properties of the drugs. Each of these factors is defined and examples are given. In particular, the various quantum-chemical procedures (ab-initio, approximately rigorous, semirigorous, semiempirical, and empirical) used to calculate the electronic structures of isolated and solvated drugs and biomolecules and their intermolecular interactions are described and their relative merits or deficiencies evaluated. The procedures used to correlate or to predict structure–activity relationships of drugs [pattern recognition and cluster analysis, multivariate statistical analysis including linear free energy relationships (LFER), as well as parabolic and other] are discussed. It is proven that the proper lipophilicity index to use is not the partition coefficient, which is pH independent, but rather the true drug distribution coefficient (or apparent partition coefficient) which is pH dependent. The importance of its temperature dependence is also stressed. Common misconceptions concerning the relationship of quantum chemically calculated electron densities to such experimentally measured properties as pKK and 13C and 15N nuclear magnetic resonance shifts are pointed out, and the appropriate formulations are indicated.