Fig. 1. Correlation between observed and calculated log P_e values. Compounds depicted as grey dots have experimental permeability values which are below the limit of quantification of the UV analytics. They were arbitrarily set to log P_e values of −9 (see text for more details).

Fig. 2. VIP plot from PLS analysis using four descriptors, two extended descriptors and one binned descriptor. The descriptors used for model generation are the calculated atom charge at the quaternary nitrogen (nitrogen_ch), the “thickness” of the molecule divided by its “length” (d0_d2) as a kind of “globularity” measure, the “width” of a molecule (d1), the positive variance of the molecular electronic potential (MepVarPos) and the presence of acidic functions in the molecules (A_0, no acidic group; A_1, one acidic group, A_2, two acidic groups).

Fig. 3. Centered and scaled coefficients of five variables and two extended variables. The meaning of the bars for the indicator variables A0, A1, A2 is described in more detail. The negative coefficient of A0 shows that molecules with no acidic function give rise to lower permeability values. The positive coefficient of A1 indicate that one acidic function give rise to higher permeability values and the negative coefficient for A2 illustrates that the presence of a second acidic function leads to lower permeability values. All the other abbreviations are described in Fig. 2.

Overview of descriptors which were used in Model M2 (cf. Table 3)

Experimental permeability values together with the distribution of the compound in the acceptor, membrane and donor compartment, at pH 6.5

In silico P-gp assessment according to Seelig (1998).

Overview of PLS models

Comparison between ethidium and 2-N-methylellipticinium