Fraction Lipophilicity Index (FLI). A drug-like metric for orally administered ionizable drugs

Fraction Lipophilicity Index (FLI) was developed as a metric for assessing drug likeness of ionizable oral drugs. Considering that both log <i>P</i> and log <i>D</i> have distinct roles in drug action, the metric FLI allocates lipophilicity to a pH dependent neutral fraction of the molecule and is a weighted combination of log <i>P</i> and log <i>D</i>. It is expressed by equation: FLI = 2 x log <i>P</i>–│log <i>D</i>│. A dataset of 368 basic and acidic drugs was analyzed. Based on available % absorption data, drugs were classified into class 1 (268 drugs) and class 2 (100 drugs). The freeware MedChem Designer was used for log <i>P</i> and log <i>D</i> calculations at pH 7.4 and pH 5.5 for acids. Based on class 1, a drug-like FLI range 0–8 was defined. FLI distribution for class 2 is shifted towards significantly lower values. Comparison of FLI with rule of 5 (Ro5) shows that it leads to fewer values outside the established range than the corresponding log <i>P</i> violations for class 1. For class 2 it gives more alerts than Ro5 and can be considered complementary to Ro5, while it also sets lower limits to discriminate drugs with poor absorption.