Abstract
Fraction Lipophicity Index (FLI) has been developed as a composite drug-like metric combining log P and log D in a weighted manner. In the present study, an extended data set confirmed the previously established drug-like FLI range 0-8 using two calculation systems for log P/log D assessment, the freeware MedChem Designer and ClogP. The dataset was split into two classes according to the percentage of fraction absorbed (%FA) - class 1 including drugs with high to medium absorption levels and class 2 including poorly absorbed drugs. The FLI and FLI-C (ClogP based FLI) drug-like range covers 92 % and 91 % of class 1 drugs, respectively. Using MlogP, a narrower drug-like FLI-M range 0-7 was established, covering 91 % of class 1 drugs. The dependence of the degree of ionization to intrinsic lipophilicity within the FLI (FLI-C, FLI-M) drug-like range as well as the inter-relation between the other Ro5 properties (Mw, HD, HA) was explored to define drug-like / non-drug-like combinations as a safer alternative to single properties for drug candidates’ prioritization. In this sense, we propose a combined metric of Mw and the number of polar atoms (Mw/NO) to account for both size and polarity. Setting the value 50 as cutoff, a distinct differentiation between class 1 and class 2 drugs was obtained with Mw/NO>50 for more than 70 % of class 1 drugs, while the opposite was observed for class 2 drugs.
Highlights
The role of physicochemical properties in controlling the fate of drug molecules within the organism and their binding to macromolecules has been well documented
We propose a combined metric of molecular weight (Mw) and the number of polar atoms (Mw/NO) to account for both size and polarity
Application of three different methods, MedChem Designer, ClogP and MlogP for lipophilicity assessment in Fraction Lipophilicity Index (FLI) generation, supported the robustness of the results while showing that the metric is overall independent of log P calculation system
Summary
The role of physicochemical properties in controlling the fate of drug molecules within the organism and their binding to macromolecules has been well documented. There is strong evidence that compounds with higher lipophilicity and higher molecular weight, e.g., with high molecular ‘obesity’ are more likely to be discontinued during clinical development [3,4,5,6]. They are associated with difficulties in oral absorption, while they are considered to exhibit increased ‘promiscuity’ towards biomacromolecules.
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