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Predicting partition coefficients of drug-like molecules in the SAMPL6 challenge with Drude polarizable force fields

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Abstract

The water-octanol partition coefficient is an important physicochemical property for small molecule drug design. Here, we report our participation in the SAMPL6 logP prediction challenge with free energy perturbation (FEP) calculations in the water phase and in the 1-octanol phase using Drude polarizable force fields. Root mean square error (RMSE) and mean absolute error (MAE) of our prediction are equal to 1.85 and 1.25 logP units. The errors are not evenly distributed. Out of eleven SAMPL6 solutes, FEP/Drude performed very badly on three molecules (deviations all larger than 2 logP units) but good on the remaining eight (deviations all less than 1 logP unit). We find while FEP converges well within one nanosecond in water, simulations in 1-octanol need much longer simulation time and possibly more independent runs for sampling. We also find out that 1-octanol, albeit being a non-polar solvent, still polarizes solute molecules and forms stable hydrogen bonds with them. At the end, we attempt to reweight FEP trajectories with QM/Drude calculations and discuss possible caveats in our simulation setup.

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Acknowledgements

The work is supported by National Natural Science Foundation of China (Grant No. 21803057) and by Zhejiang Provincial Natural Science Foundation of China (Grant No. LR19B030001). We acknowledge the usage of the HPC cluster of Westlake University.

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  1. Key Laboratory of Structural Biology of Zhejiang Province, School of Life Sciences, Westlake University, 18 Shilongshan Road, Hangzhou, 310024, Zhejiang Province, China

    Ye Ding, You Xu, Cheng Qian, Jinfeng Chen, Jian Zhu, Houhou Huang, Yi Shi & Jing Huang

  2. Institute of Biology, Westlake Institute for Advanced Study, 18 Shilongshan Road, Hangzhou, 310024, Zhejiang Province, China

    Ye Ding, You Xu, Cheng Qian, Jinfeng Chen, Jian Zhu, Houhou Huang, Yi Shi & Jing Huang

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Ding, Y., Xu, Y., Qian, C. et al. Predicting partition coefficients of drug-like molecules in the SAMPL6 challenge with Drude polarizable force fields. J Comput Aided Mol Des 34, 421–435 (2020). https://doi.org/10.1007/s10822-020-00282-5

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