Partition coefficients and drug discovery

(on tour in rural Wisconsin)

Peter W Kenny http://fbdd-lit.blogspot.com | http://www.slideshare.net/pwkenny

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

Molecular interactions and drug action

In tissues

Free in

plasma

Bound to

plasma

protein

Dose of drug

Eliminated drug

What happens to drugs after dosing

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…

Lipophilic & half ionised Hydrophilic & neutral

Introduction to partition coefficients

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

Octanol/Water Alkane/Water

Octanol/water is not the only partitioning system

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

-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

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

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

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

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

Structural relationships between compounds as a framework for molecular design

Examples of structural relationships between compounds

Tanimoto coefficient (foyfi) for structures is 0.90

Ester is methylated acid Amides are ‘reversed’

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

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

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?

• 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