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.
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
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
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
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