Validation of a biophysical drug absorption model by the PATQSAR system.

Absorption rate constants (in situ rat gut technique) and in vitro antibacterial activities of twenty fluoroquinolones have been evaluated. A biophysical model that relates the absorption of the compounds with their lipophilicity was fitted. The model considers the absorption process from the intestinal lumen as the sum of two resistances in series: aqueous diffusional barrier and lipoidal membrane. Even if partitioning into the membrane and membrane diffusion are both enhanced for lipophilic compounds, the absorption rate constant is limited by the aqueous diffusion. To estimate the influence of structural modifications on each property and to establish the role of lipophilicity in controlling in situ absorption and in vitro antibacterial activity, the PATQSAR search system is used to construct structure-property relationships. The structural models, which explain 99% of the total variance of each physicochemical property and 96% of each in vitro biological activity, provide an explicit and precise interpretation of lipophilicity, absorption, and antimicrobial activity. The results confirm the important role of lipophilicity in controlling absorption, as pointed out by the biophysical model for the piperazinyl series, and suggest the introduction of electronic factors in order to extend the model to heterologues. They also justify the mechanism by which quinolones are assumed to induce antibacterial activity.

Enhancing the flexibility and adaptability of the DARC structural representation for computer-aided drug design.

Noticeable progress has been achieved in the determination of dynamic topochromatic variables for the structural representation of compounds and their situation in a given population. These independent structural variables can be further combined into more complex variables. Their contributions to the evolution of an associated property can therefore be evaluated with certainty. The risk of having correlated variables is avoided while the structural description remains exhaustive. In order to enhance the interpretative ability of the QSAR model, one or several physicochemical properties can be taken with these structural parameters as explanatory variables. Typically, partition coefficients, 3-D and quantum mechanical data are used for this purpose. The structural aspects not taken into account by the physicochemical parameters are reflected in the remaining topochromatic variables. The use of these new concepts is presented in a study of carbazole mutagenicity. The model explains 99% of the total variance with one external property and four additional topochromatic variables. The modulation of the heat of formation of an intermediate by two topochromatic variables suggests a much more precise interpretation than a simple combination of the usual external variables.