It Is Not Just A Numberit Is A Multimechanism

Drugs exert their therapeutic effects through reactions with specific receptors. Drug-receptor binding depends on the concentration of the drug near the receptor. Its form and concentration near the receptor depend on its physical properties. Orally administered drugs need to be dissolved at the site of absorption in the gastrointestinal tract (GIT), and need to traverse several membrane barriers before receptor interactions can commence. As the drug distributes into the various compartments of the body, a certain (small) portion finds itself at the receptor site. Transport and distribution of most drugs are affected by passive diffusion, which depends on lipophilicity, since lipid barriers need to be crossed [19-24]. Passive transport is well described by the principles of physical chemistry [25-33].

The pKa of a molecule, a charge-state-related parameter, is a descriptor of an acid-base equilibrium reaction [34,35]. Lipophilicity, often represented by the octanol-water partition coefficient Kp is a descriptor of a two-phase distribution equilibrium reaction [36]. So is solubility [37-39]. These three parameters are thermodynamic constants. On the other hand, permeability Pe is a rate coefficient, a kinetics parameter, most often posed in a first-order distribution reaction [40-42].

In high-throughput screening (HTS) these parameters are sometimes viewed simply as numbers, quickly and roughly determined, to be used to rank molecules into ''good'' and ''bad'' classes. An attempt will be made to examine this important aspect. In addition, how fundamental, molecular-level interpretations of the physical measurements can help to improve the design of the profiling assays will be examined, with the aim of promoting the data fodder of HTS to a higher level of quality, without compromising the need for high speed. Quality measurements in large quantities will lead to improved in silico methods. Simple rules (presented in visually appealing ways), in the spirit of Lipinski's rule of fives, will be sought, of use not only to medicinal chemists but also to preformulators [12,43]. This book attempts to make easier the dialog between the medicinal chemists charged with modifying test compounds and the pharmaceutical scientists charged with physico-chemical profiling, who need to communicate the results of their assays in an optimally effective manner.

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