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

Molecules : a Journal of Synthetic Chemistry and Natural Product Chemistry
Koji OgataShinichiro Nakamura

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 determini...Continue Reading

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Citations

Feb 1, 2020·Journal of Computer-aided Molecular Design·Jonathan A Ouimet, Andrew S Paluch
Aug 30, 2020·Pharmaceuticals·Rozires P LeãoCleydson B R Santos
Jun 25, 2021·Journal of Chemical Information and Modeling·Panagiotis C PetrisJohannes G E M Fraaije
Jul 11, 2021·Journal of Computer-aided Molecular Design·Fabio FalcioniRichard H Henchman

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