The document discusses the importance of lipophilicity in molecular design, particularly in drug discovery and development, outlining challenges faced by the pharmaceutical industry such as unpredictable toxicity and difficulties in measuring unbound drug concentrations. It emphasizes that hydrogen bonding is a significant determinant of lipophilicity and highlights alternatives to the octanol/water partitioning system, suggesting the relevance of alkane/water systems. Key findings include the correlation of molecular electrostatic potential with hydrogen bond properties and the implications for drug affinity and permeability.

1. Lipophilicity in the context of Molecular Design
Peter W Kenny (pwk.pub.2008@gmail.com)

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. Molecular Interactions and Drug Action

4. Cartoon representation of hydrophobic effect
Polar Surface
Binding Pocket

5. Cartoon representation of hydrophobic forces

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. 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. 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. 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. Fluorine: A weak hydrogen bond acceptor
-0.122 -0.113 -0.071
-0.038

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. r
Donors: The Va(r) descriptor
Calculate electrostatic
potential (V) at this point

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. 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. 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. Octanol was the first mistake...

17. Lipophilic & half ionised Hydrophilic
Introduction to partition coefficients

18. Polarity
N
ClogP ≤ 5 Acc ≤10; Don ≤5
An alternative view of the Rule of 5

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. Octanol/Water Alkane/Water
Octanol/water is not the only partitioning system

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. 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. 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. 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. 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. logPalk as perturbation of value for saturated hydrocarbon
MSA/Å2
Alkanes
Alkanols

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. 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. 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