partition coefficients in drug discovery
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Transcript of partition coefficients in drug discovery
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Partition coefficients and drug discovery
(on tour in rural Wisconsin)
Peter W Kenny http://fbdd-lit.blogspot.com | http://www.slideshare.net/pwkenny
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Molecular Design
• Control of behavior of compounds and materials by
manipulation of molecular properties
• Hypothesis-driven or prediction-driven
• Sampling of chemical space
– For example, does fragment-based screening allow better
control of sampling resolution?
Kenny, Montanari, Propopczyk, Sala, Sartori (2013) JCAMD 27:655-664 DOI
Kenny JCIM 2009 49:1234-1244 DOI
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Molecular interactions and drug action
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In tissues
Free in
plasma
Bound to
plasma
protein
Dose of drug
Eliminated drug
What happens to drugs after dosing
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Partition coefficients in drug discovery
• Octanol/water is default partitioning system• Model for cell membrane (permeability)• Generic measure of (aqueous) desolvation for
modelling actiivity, solubility…
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Lipophilic & half ionised Hydrophilic & neutral
Introduction to partition coefficients
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Does octanol/water ‘see’ hydrogen bond donors?
--0.06 -0.23 -0.24
--1.01 -0.66--1.05
Kenny & Montanari (2013) JCAMD 27:1-13 DOI
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Octanol/Water Alkane/Water
Octanol/water is not the only partitioning system
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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 (ΔlogP) in octanol/water and alkane/water logP values reflect hydrogen bonding between solute and octanol
Toulmin et al (2008) J Med Chem 51:3720-3730 DOI
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-0.054
-0.086-0.091
-0.072
-0.104 -0.093
Connection between lipophilicity and hydrogen bonding
Toulmin et al (2008) J Med Chem 51:3720-3730 DOI
DlogP = 0.5
DlogP = 1.3Minimized electrostatic potential (Vmin) values (atomic units) are predictive of hydrogen bond basicity
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logPoct = 0.97
logPalk = 1.48
logPoct = 2.17
logPalk = −0.31
logPoct = 2.23
logPalk = 0.97
logPoct = 2.42
logPalk = 0.26
logPoct = 1.66
logPalk = 1.38
logPoct = 1.35
logPalk = 2.29
logP as probe of steric and conformational effects
Dearden & Bresnen (2005) Int J Mol Sci 6:119-129 DOI
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1.0 1.1 0.8 1.3 1.7
0.8 1.5
What do these measured values of DlogP tell us?
Toulmin et al, J. Med. Chem. 2008, 51, 3720-3730
1.6 1.1
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Basis for ClogPalk model
logP
alk
MSA/Å2
Kenny, Montanari & Propopczyk et al (2013) JCAMD 27:389-402 DOIKenny, Montanari & Propopczyk et al (2013) JCAMD 27:389-402 DOI
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𝐶𝑙𝑜𝑔𝑃𝑎𝑙𝑘 = 𝑙𝑜𝑔𝑃0 + 𝑠 ×𝑀𝑆𝐴 −
𝑖
∆𝑙𝑜𝑔𝑃𝐹𝐺,𝑖 −
𝑗
∆𝑙𝑜𝑔𝑃𝐼𝑛𝑡,𝑗
ClogPalk from perturbation of saturated hydrocarbon
logPalk predicted
for saturated
hydrocarbon
Perturbation by
functional groups
Perturbation by
interactions
between
functional groups
Kenny, Montanari & Propopczyk et al (2013) JCAMD 27:389-402 DOI
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Structural relationships between compounds as a framework for molecular design
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Examples of structural relationships between compounds
Tanimoto coefficient (foyfi) for structures is 0.90
Ester is methylated acid Amides are ‘reversed’
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Hypothesis-driven molecular design and relationships between structures as framework for analysing activity and properties
?
Date of Analysis N DlogFu SE SD %increase
2003 7 -0.64 0.09 0.23 0
2008 12 -0.60 0.06 0.20 0
Mining PPB database for carboxylate/tetrazole pairs suggested that bioisosteric replacement wouldlead to decrease in Fu . Tetrazoles were not synthesised even though their logP values are expected tobe 0.3 to 0.4 units lower than for corresponding carboxylic acids.
Birch et al (2009) BMCL19:850-853 DOI
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Amide N DlogS SE SD %Increase
Acyclic (aliphatic amine) 109 0.59 0.07 0.71 76
Cyclic 9 0.18 0.15 0.47 44
Benzanilides 9 1.49 0.25 0.76 100
Effect of amide N-methylation on aqueous solubility is dependent on substructural context
Birch et al (2009) BMCL 19:850-853 DOI
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Structural relationships between compounds
Discover new
bioisosteres &
scaffolds
Prediction of activity &
properties
Recognise
extreme data
Direct
prediction
(e.g. look up
substituent
effects)
Indirect
prediction
(e.g. apply
correction to
existing model)
Bad
measurement
or interesting
effect?
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• Partition coefficients are not quite as boring as you
thought that they were
• There is life beyond octanol/water (and atom-
centered charges) if we choose to look for it
• Even molecules can have meaningful relationships
Stuff to think about