Calculation of distribution coefficients in the SAMPL5 challenge from atomic solvation parameters and surface areas Diogo Santos-Martins 1 • Pedro Alexandrino Fernandes 1 • Maria Joa ˜o Ramos 1 Received: 21 June 2016 / Accepted: 21 August 2016 Ó Springer International Publishing Switzerland 2016 Abstract In the context of SAMPL5, we submitted blind predictions of the cyclohexane/water distribution coeffi- cient (D) for a series of 53 drug-like molecules. Our method is purely empirical and based on the additive contribution of each solute atom to the free energy of solvation in water and in cyclohexane. The contribution of each atom depends on the atom type and on the exposed surface area. Comparatively to similar methods in the lit- erature, we used a very small set of atomic parameters: only 10 for solvation in water and 1 for solvation in cyclohexane. As a result, the method is protected from overfitting and the error in the blind predictions could be reasonably estimated. Moreover, this approach is fast: it takes only 0.5 s to predict the distribution coefficient for all 53 SAMPL5 compounds, allowing its application in virtual screening campaigns. The performance of our approach (submission 49) is modest but satisfactory in view of its efficiency: the root mean square error (RMSE) was 3.3 log D units for the 53 compounds, while the RMSE of the best performing method (using COSMO-RS) was 2.1 (submis- sion 16). Our method is implemented as a Python script available at https://github.com/diogomart/SAMPL5-DC- surface-empirical. Keywords SAMPL5 Á Drug design data resource Á D3R Á Solvent accessible area Á Free energy of solvation Á Distribution coefficient Introduction The free energy of solvation DG solv can be separated in (1) cavitation free energy and (2) solute–solvent interaction free energy. The cavitation free energy corresponds to the cost of disrupting solvent–solvent interactions in order to create a cavity that accommodates the solute. Solute–sol- vent interactions include van der Waals interactions and electrostatic interactions. Hydrogen bonds can be treated separately or within the general framework of electrostatic interactions. The assumption that cavitation and solute– solvent interaction free energies are additive provides a simple framework where the balance between these two terms rationalizes observed phenomena. For example, the hydrophobic effect observed for apolar solutes in water results from the high cost of forming a cavity (which includes the entropic penalty associated with constrained water molecules) and lack of counterbalancing strong solute–water interactions. The solute–solvent interaction energy is mostly deter- mined by the first layer of solvent molecules and by exposed solute atoms, simply because atoms in close proximity make the largest vdW and electrostatic contri- bution (charged buried atoms, such as in transition metal complexes, may be exceptions to this general rule). Moreover, if the solvent has hydrogen bond donors/ Electronic supplementary material The online version of this article (doi:10.1007/s10822-016-9951-y) contains supplementary material, which is available to authorized users. & Diogo Santos-Martins diogom@fc.up.pt Pedro Alexandrino Fernandes pafernan@fc.up.pt Maria Joa ˜o Ramos mjramos@fc.up.pt 1 UCIBIO, REQUIMTE, Departamento de Quı ´mica e Bioquı ´mica, Faculdade de Cie ˆncias, Universidade do Porto, 4169-007 Porto, Portugal 123 J Comput Aided Mol Des DOI 10.1007/s10822-016-9951-y