Lipophilicity in the context of molecular design

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I did this talk at Simpósio de Simulação Computacional e Avaliação Biológica de Biomoléculas na Amazônia (SSCABBA) in Belem on 12-Sept-2012. The photograph in the title slide was taken in Asunción.

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Lipophilicity in the context of molecular design

  1. 1. Lipophilicity in the context of Molecular Design Peter W Kenny (pwk.pub.2008@gmail.com)
  2. 2. Some things that are hurting Pharma • Having to exploit targets that are less well-linked to human disease • Inability to predict idiosyncratic toxicity • Inability to measure free (unbound) physiological concentrations of drug for remote targets (e.g. intracellular or within blood brain barrier) Dans la merde: http://fbdd-lit.blogspot.com/2011/09/dans-la-merde.html
  3. 3. Molecular Interactions and Drug Action
  4. 4. Cartoon representation of hydrophobic effect Polar Surface Binding Pocket
  5. 5. Cartoon representation of hydrophobic forces
  6. 6. Hydrogen Bonding Interactions between drug molecules in crystal lattice (Solubility, melting point polymorphism, crystallinity) Interactions between drug and water molecules (Solubility, distribution, permeability, potency, toxicity, efflux, metabolism) Interactions between drug molecules & (anti)target(s) (Potency, toxicity, efflux , metabolism, distribution) Hydrogen Bonding in Drug Discovery & Development Interactions between water molecules (Hydrophobic effect)
  7. 7. bond basicity  Plot of V/kJmol-1 against r/Å for pyridine on lone pair axis showing electrostatic potential minimum 1.2Å from nitrogen -300 -200 -100 0 V 0 1 2 3 4 5 r Electrostatic potential as function of position for acceptor V/kJmol-1 r/Å
  8. 8. Comparison of Vmin and pKa as predictors of logKb logKb Vmin/(Hartree/electron) pKa Heteroaromatic nitrogen in five and six-membered rings Kenny JCS Perkin Trans 2 1994, 199-202
  9. 9. 1.01 1.16 0.94 0.40 0.06 2.63 1.53 2.50 1.89 1.82 2.39 Predicted logKb 2.64 1.68 2.51 1.90 2.50 Measured logKb 2.38 1.98 2.36 2.17 1.99 Non-equivalent acceptors provide validation set Kenny JCS Perkin Trans 2 1994, 199-202
  10. 10. Fluorine: A weak hydrogen bond acceptor -0.122 -0.113 -0.071 -0.038
  11. 11. -0.054 -0.086 -0.091 -0.072 -0.104 -0.093 Hydrogen bonding of esters Toulmin et al, J. Med. Chem. 2008, 51, 3720-3730
  12. 12. r Donors: The Va(r) descriptor Calculate electrostatic potential (V) at this point
  13. 13. Va(r) as predictor of logKa Sensitivity to distance from donor hydrogen Va/(Hartree/electron) Va/(Hartree/electron) logKa logKa r = 0.55 Å r = 1.20 Å R2 = 0.65 RMSE = 0.43 R2 = 0.93 RMSE = 0.20 Kenny, JCIM, 2009, 49, 1234-1244
  14. 14. Effect of complex formation on Vmin Toulmin et al, J. Med. Chem. 2008, 51, 3720-3730 -0.092 -0.103 -0.125 -0.097 -0.078 -0.092 -0.114 -0.113 -0.115 -0.127
  15. 15. H O H H O H H O H H O H N H O Effect of complex formation on predicted logKa 1.2 (~ Alcohol) 2.0 (~ Phenol) 2.8 (~ 4-CF3Phenol) Kenny, JCIM, 2009, 49, 1234-1244
  16. 16. Octanol was the first mistake...
  17. 17. Lipophilic & half ionised Hydrophilic Introduction to partition coefficients
  18. 18. Polarity N ClogP ≤ 5 Acc ≤10; Don ≤5 An alternative view of the Rule of 5
  19. 19. Does octanol/water ‘see’ hydrogen bond donors? --0.06 -0.23 -0.24 --1.01 -0.66 Sangster lab database of octanol/water partition coefficients: http://logkow.cisti.nrc.ca/logkow/index.jsp --1.05
  20. 20. Octanol/Water Alkane/Water Octanol/water is not the only partitioning system
  21. 21. logPoct = 2.1 logPalk = 1.9 DlogP = 0.2 logPoct = 1.5 logPalk = -0.8 DlogP = 2.3 logPoct = 2.5 logPalk = -1.8 DlogP = 4.3 Differences in octanol/water and alkane/water logP values reflect hydrogen bonding between solute and octanol Toulmin et al, J. Med. Chem. 2008, 51, 3720-3730
  22. 22. 1.0 1.1 0.8 1.3 1.7 0.8 1.5 Measured values of DlogP Toulmin et al, J. Med. Chem. 2008, 51, 3720-3730 1.6 1.1
  23. 23. DlogP (corrected) Vmin/(Hartree/electron) DlogP (corrected) Vmin/(Hartree/electron) N or ether O Carbonyl O logPalk as perturbation of logPoct Prediction of contribution of acceptors to DlogP Toulmin et al, J. Med. Chem. 2008, 51, 3720-3730 DlogP = DlogP0 x exp(-kVmin)
  24. 24. logPoct = 0.89 predicted logPalk = -4.2 PSA/Å2 = 53 logPoct = 1.58 predicted logPalk = -1.4 PSA/Å2 = 65 Lipophilicity/polarity of Morphine & Heroin Toulmin et al, J. Med. Chem. 2008, 51, 3720-3730
  25. 25. logPhxdlogPoct log(Cbrain/Cblood) DlogP Prediction of blood/brain partitioning R2 = 0.66 RMSE = 0.54 R2 = 0.82 RMSE = 0.39 R2 = 0.88 RMSE = 0.32 Toulmin et al, J. Med. Chem. 2008, 51, 3720-3730
  26. 26. logPalk as perturbation of value for saturated hydrocarbon MSA/Å2 Alkanes Alkanols
  27. 27. Summary • Lipophilicity is relevant to both permeability and affinity • Octanol/water is not the only partitioning system and alkane/water may be more relevant in Drug Discovery • Hydrogen bonding is an important determinant of lipophilicity • Hydrogen bonding is essentially electrostatic in nature and molecular electrostatic potential is a useful predictor of hydrogen bond acidity & basicity
  28. 28. Measuring hydrogen bond strength Acceptors Donors pKHB logKb logKa (CH3CCl3)(CCl4) Taft et al , JACS 1969, 91, 4801-4808 Laurence & Berthelot, Perspect. Drug. Discov. Des. 2000, 18, 39-60. Abraham et al, JCS Perkin Trans 2 1989, 1355-1375 (CH3CCl3) Abraham et al, JCS Perkin Trans 2 1989, 1355-1375
  29. 29. logKb: Heteroaromatic nitrogen Azines pKa 5.22 9.70 2.24 1.23 0.65 logKb 2.52 3.54 2.53 1.67 1.46 Azoles pKa 7.25 2.09 0.80 -2.03 logKb 3.68 2.22 1.67 1.06 Abraham et al, JCS Perkin Trans 2 1989, 1355-1375

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