Drug-like Properties and Fraction Lipophilicity Index as a combined metric

ADMET and DMPK

article

Vassilis Demopoulos¹  Anna Tsantili-Kakoulidou² 

[1] Department of Pharmaceutical Chemistry, School of Pharmacy, Aristotle University of Thessaloniki;Department of Pharmaceutical Chemistry, School of Pharmacy, National and Kapodistrian University of Athens

关键词: drug-likeness;    oral drugs;    Fraction Lipophilicity Index;    Rule of 5;    Molecular weight;    Polar atoms;   

DOI  :  10.5599/admet.1022

学科分类：社会科学、人文和艺术（综合）

来源: International Association of Physical Chemists (IAPC)

【 摘 要 】

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.

【 授权许可】

CC BY