A blind SAMPL6 challenge: insight into the octanol-water partition coefficients of drug-like molecules via a DFT approach


In this study quantum mechanical methods were used to predict the solvation energies of a series of drug-like molecules both in water and in octanol, in the context of the SAMPL6 n-octanol/water partition coefficient challenge. In pharmaceutical design, n-octanol/water partition coefficient, LogP, describes the drug’s hydrophobicity and membrane permeability, thus, a well-established theoretical method that rapidly determines the hydrophobicity of a drug, enables the progress of the drug design. In this study, the solvation free energies were obtained via six different methodologies (B3LYP, M06-2X and ωB97XD functionals with 6-311+G** and 6-31G* basis sets) by taking into account the environment implicitly; the methodology chosen (B3LYP/6-311+G**) was used later to evaluate ΔGsolv by using explicit water as solvent. We optimized each conformer in different solvents separately, our calculations have shown that the stability of the conformers is highly dependent on the solvent environment. We have compared implicitly and explicitly solvated systems, the interaction of one explicit water with drug-molecules at the proper location leads to the prediction of more accurate LogP values.

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Calculations reported in this paper were partially performed using the computational resources at CCBG funded by Bogazici University and as well as the resources of the TUBITAK ULAKBIM High Performance and Grid Computing Center (TRUBA resources).

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Arslan, E., Findik, B.K. & Aviyente, V. A blind SAMPL6 challenge: insight into the octanol-water partition coefficients of drug-like molecules via a DFT approach. J Comput Aided Mol Des 34, 463–470 (2020). https://doi.org/10.1007/s10822-020-00284-3

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  • SAMPL6
  • Octanol/water partition coefficient
  • Computer-aided drug design
  • DFT
  • Solvation free energies