Effect of Atomic Charges on Octanol-Water Partition Coefficient Using Alchemical Free Energy Calculation.

Koji Ogata,Shinichiro Nakamura,Makoto Hatakeyama

doi:10.3390/molecules23020425

Koji Ogata, Shinichiro Nakamura + Show 1 more

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https://doi.org/10.3390/molecules23020425

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Abstract

The octanol–water partition coefficient (logPow) is an important index for measuring solubility, membrane permeability, and bioavailability in the drug discovery field. In this paper, the logPow values of 58 compounds were predicted by alchemical free energy calculation using molecular dynamics simulation. In free energy calculations, the atomic charges of the compounds are always fixed. However, they must be recalculated for each solvent. Therefore, three different sets of atomic charges were tested using quantum chemical calculations, taking into account vacuum, octanol, and water environments. The calculated atomic charges in the different environments do not necessarily influence the correlation between calculated and experimentally measured ∆Gwater values. The largest correlation coefficient values of the solvation free energy in water and octanol were 0.93 and 0.90, respectively. On the other hand, the correlation coefficient of logPow values calculated from free energies, the largest of which was 0.92, was sensitive to the combination of the solvation free energies calculated from the calculated atomic charges. These results reveal that the solvent assumed in the atomic charge calculation is an important factor determining the accuracy of predicted logPow values.

Highlights

The octanol–water partition coefficient is an index used in drug discovery processes to estimate the solubility, membrane permeability, and bioavailability of compounds [1,2].Several experimental methods for measuring it have been developed [2,3,4,5,6], but they are time consuming and costly, because experimental methods use the actual compounds, and sometimes, the synthesis of a compound takes a long time
A logPow calculation method using alchemical free energy calculation with the Bennett’s acceptance ratio (BAR) method was proposed, and the results showed good agreement with the values measured experimentally
The correlation of logPow values was sensitive to the combination of the ∆Gwater and ∆Goctanol values

Summary

Introduction

The octanol–water partition coefficient (logPow ) is an index used in drug discovery processes to estimate the solubility, membrane permeability, and bioavailability of compounds [1,2]. Several experimental methods for measuring it have been developed [2,3,4,5,6], but they are time consuming and costly, because experimental methods use the actual compounds, and sometimes, the synthesis of a compound takes a long time. To accelerate the drug discovery process and to reduce its cost, we need a logPow measurement method that is easier, faster, and more accurate than the current ones

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