Prediction of n-Octanol/Water Partition Coefficients in the SAMPL6 Challenge

1. Predictionof then-Octanol/WaterPartitionCoefficients in the SAMPL6 Challengefrom MST Continuum SolvationCalculations William J. Zamora R. Collaborators: Dra. SilvanaPinheiro Prof.CarlesCurutchet Prof. Clara Ràfols Mentor: Prof. F. J. Luque La Jolla, CA. Aug 2019

2. OUTLINE • INTRODUCTION • The MST Solvation Model for Solvation Computations. • Recent Lipophilic Computations using MST Model. • Refinement for Nitrogen-Containing Heterocyclic Compounds. • 2. RESULTS • Our Performance in the SAMPL6 Challenge. • Analysis of the Main Outliers. • 3. CONCLUSIONS SAMPL6 CHALLENGE Prediction of the n-Octanol/WaterPartitionCoefficients in the SAMPL6 Challengefrom MST Continuum SolvationCalculations

3. INTRODUCTION The MST Solvation Model for Solvation Computations Continuum SolvationModel QM Self-Consistent Reaction Field (SCRF)  SAMPL6 CHALLENGE Models B3LYP/6-31G(d) HF/6-31G(d) SemiempiricalAM1 and PM3 Solvents water, dimethylsulfoxide, n-octanol, chloroformand carbontetrachloride Prediction of the n-Octanol/WaterPartitionCoefficients in the SAMPL6 Challengefrom MST Continuum SolvationCalculations

4. INTRODUCTION The MST Solvation Model for Solvation Computations Pierotti’s scaled particle theory & Claverieprocedure Cav Solvent Solute Solvent vdW surface SAMPL6 CHALLENGE vdW surface vdW Ele λ Prediction of the n-Octanol/WaterPartitionCoefficients in the SAMPL6 Challengefrom MST Continuum SolvationCalculations

5. INTRODUCTION Recent Lipophilic Computations using MST Model SAMPL6 CHALLENGE Prediction of the n-Octanol/WaterPartitionCoefficients in the SAMPL6 Challengefrom MST Continuum SolvationCalculations

6. INTRODUCTION Refinement for Nitrogen-Containing HeterocyclicCompounds SAMPL6 CHALLENGE Original (kcal mol-1Å-2) Refined (kcal mol-1Å-2) Prediction of the n-Octanol/WaterPartitionCoefficients in the SAMPL6 Challengefrom MST Continuum SolvationCalculations

7. INTRODUCTION Refinement for Nitrogen-Containing Aromatic Compounds SAMPL6 CHALLENGE rsmd = 0.8 Prediction of the n-Octanol/WaterPartitionCoefficients in the SAMPL6 Challengefrom MST Continuum SolvationCalculations

8. RESULTS SAMPL6 Compounds SAMPL6 CHALLENGE Prediction of the n-Octanol/WaterPartitionCoefficients in the SAMPL6 Challengefrom MST Continuum SolvationCalculations

9. RESULTS Our Performance in the SAMPL6 Challenge MST CBDD Group Barcelona SAMPL6 CHALLENGE Prediction of the n-Octanol/WaterPartitionCoefficients in the SAMPL6 Challengefrom MST Continuum SolvationCalculations

10. RESULTS Our Performance in the SAMPL6 Challenge MST CBDD Group Barcelona SAMPL6 CHALLENGE Prediction of the n-Octanol/WaterPartitionCoefficients in the SAMPL6 Challengefrom MST Continuum SolvationCalculations

11. RESULTS Our Performance in the SAMPL6 Challenge SAMPL6 CHALLENGE Prediction of the n-Octanol/WaterPartitionCoefficients in the SAMPL6 Challengefrom MST Continuum SolvationCalculations

12. RESULTS Our Performance in the SAMPL6 Challenge SAMPL6 CHALLENGE Prediction of the n-Octanol/WaterPartitionCoefficients in the SAMPL6 Challengefrom MST Continuum SolvationCalculations

13. RESULTS Analysis of the Main Outliers: SM08 SAMPL6 CHALLENGE Comp. log PN Exptl. log PN 4.69 3.87 3.10 Prediction of the n-Octanol/WaterPartitionCoefficients in the SAMPL6 Challengefrom MST Continuum SolvationCalculations

14. RESULTS Analysis of the Main Outliers: SM08 SAMPL6 CHALLENGE Prediction of the n-Octanol/WaterPartitionCoefficients in the SAMPL6 Challengefrom MST Continuum SolvationCalculations

15. RESULTS Analysis of the Main Outliers: SM08 SAMPL6 CHALLENGE Exptl. log PN 3.10 Carey, A.R et al. Keto-Enol and Imine-EnamineTautomerism of 2-, 3- and 4 Phenacylpyridines. . J. Chem. Soc. PerkinTrans. 2. 1993, 2285-2296 Kleinpeter, E. (2013). NMR SpectroscopicStudy of Tautomerism in Solution and in the Solid State. Tautomerism, 103–143. Prediction of the n-Octanol/WaterPartitionCoefficients in the SAMPL6 Challengefrom MST Continuum SolvationCalculations

16. RESULTS Analysis of the Main Outliers: SM13 SAMPL6 CHALLENGE Exptl. log PN 2.92 3.03 Comp. log PN 4.28 3.21 Prediction of the n-Octanol/WaterPartitionCoefficients in the SAMPL6 Challengefrom MST Continuum SolvationCalculations

17. RESULTS Analysis of the Main Outliers: SM13 Table 2. Experimental conditionsforthe potentiometricdetermination of log PN SAMPL6 CHALLENGE Prediction of the n-Octanol/WaterPartitionCoefficients in the SAMPL6 Challengefrom MST Continuum SolvationCalculations

18. RESULTS Analysis of the Main Outliers: SM13 SAMPL6 CHALLENGE Exptl. log PN 4.57 ± 0.09 Comp. log PN 4.28 Prediction of the n-Octanol/WaterPartitionCoefficients in the SAMPL6 Challengefrom MST Continuum SolvationCalculations

19. RESULTS Analysis of the Main Outliers: SM15 pKas = 4.7 & 8.9 Exptl. log PN 3.07 1.95 SAMPL6 CHALLENGE Comp. log PN 1.81 1.77 Ràfols, C et al. Criticalcomparison of shake-flask, potentiometric and chromatographicmethodsfor lipophilicity evaluation (log Po/w) of neutral, acidic, basic, amphoteric, and zwitterionicdrugs. Eur J PharmSci. 2018, 122, 331-340. Prediction of the n-Octanol/WaterPartitionCoefficients in the SAMPL6 Challengefrom MST Continuum SolvationCalculations

20. RESULTS Analysis of the Main Outliers: SM13 SAMPL6 CHALLENGE Prediction of the n-Octanol/WaterPartitionCoefficients in the SAMPL6 Challengefrom MST Continuum SolvationCalculations

21. CONCLUSION • The refinements made in the MST method for the treatment of solutes in n-octanol improve the ability of the model for predicting partitioningsof neutral compounds. • The performance of the MST model was successful and could be improved considering tautomeric forms and reviewing some experimental values • For the sake of validation and comparison, it is recommended for zwitterion compounds perform an extra measurement by a standard technique such as shake flask SAMPL6 CHALLENGE Prediction of the n-Octanol/WaterPartitionCoefficients in the SAMPL6 Challengefrom MST Continuum SolvationCalculations

22. Acknowledgments Mentor: Dr. F. Javier Luque Collaborators: Dra. SilvanaPinheiro Dr. CarlesCurutchet Dra. Clara Ràfols Dr. Martí Rosés

23. Hamiltonian of theSolute Ben-Naim’sdefinition of a solvationprocess Assumptions ele + n-ele Thecouplingbetweenrepulsion and electrostaticsisexpectedto be small Thatdispersionisweaklycoupledtoelectrostatics, at leastfor neutral solutes and polar solvents CavitationEnergy Pierotti’sScaledParticleTheory Claverie’sScaledParticleTheory Sphericmolecules Complexshapemolecules

24. Dispersion–RepulsionEnergy

25. ElectrostaticEnergy