Tsantili-Kakoulidou Anna, Demopoulos Vassilis J
Department of Pharmaceutical Chemistry, School of Pharmacy, National and Kapodistrian University of Athens, Panepistimiopolis, Zografou, 157 71 Athens, Greece. E-mail:
Department of Pharmaceutical Chemistry, School of Pharmacy, Aristotle University of Thessaloniki, 54124 Thessaloniki, Greece. E-mail:
ADMET DMPK. 2021 Oct 10;9(3):177-190. doi: 10.5599/admet.1022. eCollection 2021.
Fraction Lipophicity Index (FLI) has been developed as a composite drug-like metric combining log and log 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 /log 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.
分数脂溶性指数（FLI）已被开发为一种综合的类药指标，以加权方式结合了log 和log 。在本研究中，一个扩展数据集使用两种用于log /log 评估的计算系统——免费软件MedChem Designer和ClogP，证实了先前确定的类药FLI范围为0 - 8。根据吸收分数（%FA）的百分比将数据集分为两类——第1类包括高至中等吸收水平的药物，第2类包括吸收较差的药物。FLI和基于ClogP的FLI（FLI - C）类药范围分别覆盖了第1类药物的92%和91%。使用MlogP，建立了一个更窄的类药FLI - M范围0 - 7，覆盖了第1类药物的91%。探索了FLI（FLI - C、FLI - M）类药范围内电离程度与内在亲脂性的相关性以及其他Ro五特性（分子量、氢键供体数、氢键受体数）之间的相互关系，以定义类药/非类药组合，作为一种比单一特性更安全的替代方法，用于对候选药物进行优先级排序。从这个意义上说，我们提出了一个分子量和极性原子数的组合指标（Mw/NO），以兼顾大小和极性。将50作为临界值，对于超过70%的第1类药物，Mw/NO > 50时第1类和第2类药物之间有明显区分，而第2类药物则相反。
