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Molecules 2018, 23(2), 425;

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

RIKEN Innovation Center, Nakamura Laboratory, 2-1 Hirosawa, Wako, Saitama 351-0198, Japan
Author to whom correspondence should be addressed.
Received: 19 January 2018 / Revised: 11 February 2018 / Accepted: 14 February 2018 / Published: 15 February 2018
(This article belongs to the Section Medicinal Chemistry)
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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. View Full-Text
Keywords: MD simulation; thermodynamic integration; solvation environment; atomic charge MD simulation; thermodynamic integration; solvation environment; atomic charge

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This is an open access article distributed under the Creative Commons Attribution License which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited (CC BY 4.0).

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Ogata, K.; Hatakeyama, M.; Nakamura, S. Effect of Atomic Charges on Octanol–Water Partition Coefficient Using Alchemical Free Energy Calculation. Molecules 2018, 23, 425.

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