Predicting Octanol–Water Partition Coefficients of Fluorinated Drug-Like Molecules: A Combined Experimental and Theoretical Study

Abstract

In this paper, a dataset of 11 fluorinated compounds containing a variety of functional groups (amides, esters, indoles, and ethers) as well as mono, gem-difluoro, erythro-difluoro, and threo-difluoro patterns were synthesised and their octanol–water partition coefficients (log P) were measured using a shake-flask method. The resulting data was used to assess the performance of several popular empirical fragment-based methods as well as quantum chemical implicit solvent models (SMD and SM12). Overall, the empirical miLOGP, ALOGPS, and ALOGP methods performed the best with a mean absolute deviation (MAD) of ~0.25 log units, while the best performing implicit solvent model SMD has a slightly higher MAD of 0.36 log units. Based on the present work and previous studies, the miLOGP and ALOGP empirical methods are recommended for fast and moderately accurate prediction of log P for neutral organic solutes.

Polyphenylglyoxamide-Based Amphiphilic Small Molecular Peptidomimetics as Antibacterial Agents with Anti-Biofilm Activity

“…While there are different computational methods and approaches used to estimate logP values, the AlogP method under the empirical fragment-based approaches was used in this study, as empirical fragment-based approaches are highly efficient and the AlogP method was previously demonstrated to be one of the best performing methods for estimating logP (with mean absolute errors of 0.3 log unit or less), compared to other physics-based implicit and atomistic methods [ 58 , 59 ]. The AlogP method was developed by Ghose and Crippen in 1986 and was trained on nearly 900 molecular structures [ 60 , 61 , 62 ].…”

PhysChem 2019: RACI Australian Conference on Physical Chemistry, Perth, 11–14 February 2019

“…In their article, 'Predicting Octanol-Water Partition Coefficients of Fluorinated Drug-like Molecules: A Combined Experimental and Theoretical Study', [2] Junming Ho and co-workers provide an analysis of several popular empirical fragment-based methods, and quantum chemical solvent models (SMD and SM12) which they compare against a dataset of experimentally determined octanol-water partition coefficients (log P) of functionalised fluorinated compounds (amides, esters, indoles, and ethers). They found that the empirical methods worked the best overall, with the lowest mean absolute deviations, and went on to make recommendations for fast predication of log P for neutral organic solutes with moderate accuracy.…”

Skipped Fluorination Motifs: Synthesis of Building Blocks and Comparison of Lipophilicity Trends with Vicinal and Isolated Fluorination Motifs

“…In contrast, our group reported that the two vicinal difluoride compounds C2 and C3 only gave modest lipophilicity decreases compared to the nonfluorinated parent C1 , but confirmed the irrelevance of relative stereochemistry . Hunter also recently reported that diastereoisomers of acyclic vicinal difluorinated compounds gave very similar log P values (not shown) . Nevertheless, the lipophilicity-decreasing effect of the vicinal difluoride motif introduction was convincingly demonstrated by Gilmour using Gilenya analogues. , The nonfluorinated parent with a pentoxy chain D1 is significantly more lipophilic than D2 , while the trifluoromethylated D3 only showed a modest decrease.…”

“…27 Hunter also recently reported that diastereoisomers of acyclic vicinal difluorinated compounds gave very similar log P values (not shown). 14 Nevertheless, the lipophilicity-decreasing effect of the vicinal difluoride motif introduction was convincingly demonstrated by Gilmour using Gilenya analogues. 37,38 The nonfluorinated parent with a pentoxy chain D1 is significantly more lipophilic than D2, while the trifluoromethylated D3 only showed a modest decrease.…”

“…Systematic studies exploring structure–lipophilicity relationships, especially when using actual octanol–water partition coefficient values, are thus of great interest. Such studies also have importance for data input in computational log P calculation efforts. , While every structural modification of a compound will affect its log P value, fluorine introduction has proven to be particularly useful in this regard, mainly due to a combination of its very strong electronegativity and its small size . Initiated by the seminal work of Müller and colleagues, − the influence of aliphatic chain fluorination on lipophilicities has been investigated by a number of groups, for example, by investigating new motifs − and introduction of fluorine on aliphatic systems − or in amino acid side chains. − …”