A Kinetic Basis for the Hansch Equation

The Hansch equation is a key mathematical relationship and a conceptual guiding principle (QSAR) in the practice of modern medicinal chemistry. Recent years have apparently witnessed a debate on the utility of QSAR, hence it seems opportune to explore its fundamental origins. The Hansch equation leads to a parabolic relationship between drug activity and hydrophobicity. Currently, this is explained on the basis of more efficient drug-receptor interaction at low to moderate hydrophobicity, and decreasing aqueous solubility of the drug at moderate to high hydrophobicity. Herein is presented an alternative kinetic model, essentially based on the rate of the drug-receptor interaction; thus, binding is rate determining up to moderate levels of hydrophobicity, beyond which drug release is rate determining. The overall model is based on the idea that the release of the drug occurs concurrently with a physiological response, although alternative variants are also discussed. Overall, it is argued that QSAR essentially indicates the primacy of electronic over steric effects. This has fundamental implications for the classical theory of drug-receptor binding, which may need to be appropriately reassessed. Thus, the observed structure-activity relationships possibly apply to the kinetics of drug-receptor binding, likely involving substrate-induced conformational changes within the receptor, prior to the binding event. Recent developments in receptor-based drug design methodology apparently support these views.