1 / 25

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

This study presents the use of MST continuum solvation calculations to predict the n-Octanol/Water partition coefficients in the SAMPL6 Challenge. The performance of various models and refinement techniques is analyzed, with a focus on nitrogen-containing heterocyclic and aromatic compounds. Outliers are also identified and discussed.

peterbell
Download Presentation

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

An Image/Link below is provided (as is) to download presentation Download Policy: Content on the Website is provided to you AS IS for your information and personal use and may not be sold / licensed / shared on other websites without getting consent from its author. Content is provided to you AS IS for your information and personal use only. Download presentation by click this link. While downloading, if for some reason you are not able to download a presentation, the publisher may have deleted the file from their server. During download, if you can't get a presentation, the file might be deleted by the publisher.

E N D

Presentation Transcript

  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

More Related