Prediction of the n-octanol/water partition coefficients in the SAMPL6 blind challenge from MST continuum solvation calculations

The IEFPCM/MST continuum solvation model is used for the blind prediction of n-octanol/water partition of a set of 11 fragment-like small molecules within the SAMPL6 Part II Partition Coefficient Challenge. The partition coefficient of the neutral species (log P) was determined using an extended parametrization of the B3LYP/6-31G(d) version of the Miertus–Scrocco–Tomasi continuum solvation model in n-octanol. Comparison with the experimental data provided for partition coefficients yielded a root-mean square error (rmse) of 0.78 (log P units), which agrees with the accuracy reported for our method (rmse = 0.80) for nitrogen-containing heterocyclic compounds. Out of the 91 sets of log P values submitted by the participants, our submission is within those with an rmse < 1 and among the four best ranked physical methods. The largest errors involve three compounds: two with the largest positive deviations (SM13 and SM08), and one with the largest negative deviations (SM15). Here we report the potentiometric determination of the log P for SM13, leading to a value of 3.62 ± 0.02, which is in better agreement with most empirical predictions than the experimental value reported in SAMPL6. In addition, further inclusion of several conformations for SM08 significantly improved our results. Inclusion of these refinements led to an overall error of 0.51 (log P units), which supports the reliability of the IEFPCM/MST model for predicting the partitioning of neutral compounds.

[1]  Jacopo Tomasi,et al.  A new integral equation formalism for the polarizable continuum model: Theoretical background and applications to isotropic and anisotropic dielectrics , 1997 .

[2]  H. Keenan,et al.  Effects of salinity pH and temperature on the Octanol-water partition co-efficient of Bisphenol A , 2012 .

[3]  C. Cramer,et al.  A universal approach to solvation modeling. , 2008, Accounts of chemical research.

[4]  S. Grimme.  Improved second-order Møller–Plesset perturbation theory by separate scaling of parallel- and antiparallel-spin pair correlation energies , 2003 .

[5]  J. Gautier,et al.  Considerations on the Potentiometric Log P Determination , 1998, Pharmaceutical Research.

[6]  David L. Mobley,et al.  Octanol–water partition coefficient measurements for the SAMPL6 blind prediction challenge , 2019, bioRxiv.

[7]  F. Javier Luque,et al.  Solvation in octanol: parametrization of the continuum MST model , 2001, J. Comput. Chem..

[8]  Jacopo Tomasi,et al.  Evaluation of Solvent Effects in Isotropic and Anisotropic Dielectrics and in Ionic Solutions with a Unified Integral Equation Method: Theoretical Bases, Computational Implementation, and Numerical Applications , 1997 .

[9]  William J. Zamora,et al.  Prediction of pH-Dependent Hydrophobic Profiles of Small Molecules from Miertus-Scrocco-Tomasi Continuum Solvation Calculations. , 2017, The journal of physical chemistry. B.

[10]  Giulia Caron,et al.  Lipophilicity, Polarity, and Hydrophobicity , 2007 .

[11]  C. Cramer,et al.  Universal solvation model based on solute electron density and on a continuum model of the solvent defined by the bulk dielectric constant and atomic surface tensions. , 2009, The journal of physical chemistry. B.

[12]  J. Sangster,et al.  Octanol‐Water Partition Coefficients of Simple Organic Compounds , 1989 .

[13]  Jochen Heil,et al.  Quantum chemistry in solution by combining 3D integral equation theory with a cluster embedding approach. , 2008, The journal of physical chemistry. B.

[14]  E. Bosch,et al.  Acidity and Hydrophobicity of Several New Potential Antitubercular Drugs: Isoniazid and Benzimidazole Derivatives , 2012 .

[15]  C. Cramer,et al.  Self-Consistent Reaction Field Model for Aqueous and Nonaqueous Solutions Based on Accurate Polarized Partial Charges. , 2007, Journal of chemical theory and computation.

[16]  F. J. Luque,et al.  On the performance of continuum solvation methods. A comment on "Universal approaches to solvation modeling". , 2009, Accounts of chemical research.

[17]  Donald G. Truhlar,et al.  Implicit Solvation Models: Equilibria, Structure, Spectra, and Dynamics , 1999 .

[18]  E. Bosch,et al.  Critical comparison of shake‐flask, potentiometric and chromatographic methods for lipophilicity evaluation (log Po/w) of neutral, acidic, basic, amphoteric, and zwitterionic drugs , 2018, European journal of pharmaceutical sciences : official journal of the European Federation for Pharmaceutical Sciences.

[19]  Donald G. Truhlar,et al.  Basis-set extrapolation , 1998 .

[20]  Donald G Truhlar,et al.  Generalized Born Solvation Model SM12. , 2013, Journal of chemical theory and computation.

[21]  Trygve Helgaker,et al.  Basis-set convergence in correlated calculations on Ne, N2, and H2O , 1998 .

[22]  F. J. Luque,et al.  Performance of the IEF-MST solvation continuum model in a blind test prediction of hydration free energies. , 2009, The journal of physical chemistry. B.

[23]  F. J. Luque,et al.  Lipophilicity in drug design: an overview of lipophilicity descriptors in 3D-QSAR studies. , 2019, Future medicinal chemistry.

[24]  F. Javier Luque,et al.  Fractional description of free energies of solvation , 1999, J. Comput. Aided Mol. Des..

[25]  Igor V. Tetko,et al.  Calculation of molecular lipophilicity: state of the art and comparison of methods on more than 96000 compounds , 2009 .

[26]  Xavier Barril,et al.  Physico-Chemical and Computational Approaches to Drug Discovery , 2012 .

[27]  A. Leo,et al.  Partition coefficients and their uses , 1971 .

[28]  Bernard Testa,et al.  Intramolecular Interactions Encoded in Lipophilicity: Their Nature and Significance , 2008 .

[29]  R. Mannhold,et al.  Calculation Procedures for Molecular Lipophilicity: a Comparative Study† , 1996 .

[30]  Han van de Waterbeemd,et al.  Drug bioavailability : estimation of solubility, permeability, absorption and bioavailability , 2003 .

[31]  A. Klamt.  The COSMO and COSMO‐RS solvation models , 2011 .

[32]  A. Ghose,et al.  Prediction of Hydrophobic (Lipophilic) Properties of Small Organic Molecules Using Fragmental Methods: An Analysis of ALOGP and CLOGP Methods , 1998 .

[33]  N. Howarth,et al.  Potentiometric determination of octanol–water and liposome–water partition coefficients (log P) of ionizable organic compounds , 2007 .

[34]  W. Shiu,et al.  Temperature Dependence of Octanol−Water Partition Coefficient for Selected Chlorobenzenes , 1997 .

[35]  A. Klamt,et al.  Fast solvent screening via quantum chemistry: COSMO‐RS approach , 2002 .

[36]  F. Javier Luque,et al.  Performance of the IEF-MST solvation continuum model in the SAMPL2 blind test prediction of hydration and tautomerization free energies , 2010, J. Comput. Aided Mol. Des..

[37]  P. Claverie,et al.  Studies of solvent effects , 1977 .

[38]  A. Leo.  CALCULATING LOG POCT FROM STRUCTURES , 1993 .

[39]  Xiao Wang,et al.  pKa measurements for the SAMPL6 prediction challenge for a set of kinase inhibitor-like fragments , 2018, bioRxiv.

[40]  R. Mannhold,et al.  Substructure and Whole Molecule Approaches for Calculating Log P , 2001 .

[41]  Teresa Danielle Bergazin,et al.  Assessing the accuracy of octanol-water partition coefficient predictions in the SAMPL6 Part II log P Challenge , 2020, bioRxiv.

[42]  Jacopo Tomasi,et al.  Quantum Mechanical Continuum Solvation Models , 2005 .

[43]  Pierre Tufféry,et al.  Frog2: Efficient 3D conformation ensemble generator for small compounds , 2010, Nucleic Acids Res..

[44]  F. Javier Luque,et al.  Extension of the MST model to the IEF formalism: HF and B3LYP parametrizations , 2005 .

[45]  F. Javier Luque,et al.  Continuum solvation models: Dissecting the free energy of solvation , 2003 .

[46]  R. Pierotti,et al.  A scaled particle theory of aqueous and nonaqueous solutions , 1976 .

[47]  P. Claverie,et al.  Studies of solvent effects. 1. Discrete, continuum, and discrete-continuum models and their comparison for some simple cases: ammonium(1+) ion, methanol, and substituted ammonium(1+) ion , 1978 .