hydrogen bonding and molecular design (euroqsar 2010)

Hydrogen Bonding & Molecular Design

Peter Kenny

([email protected])

QSAR: Where next?

• QSAR/QSPR models

– Hypothesis-driven design versus prediction-driven design

– Models (and descriptors) need stronger physical basis

– So do the physical models!

– How best to exploit results from assays with low dynamic range?

– How linear is molecular recognition?

• Database mining

– Focus on relationships between structures (e.g. matched molecular

pair analysis)

• Physicochemical properties

– Need access to alkane/water partition coefficients

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)

Neglect of hydrogen bond strength:

A recurring theme in medicinal chemistry

• Rule of 5

• Rule of 3

• Scoring functions for virtual screening

• Polar surface area (PSA)

• Relationships between thermodynamic properties and

buried polar & non-polar surface area

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)


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


Modelling Hydrogen Bonding

Calculate energy of

complex

• Need to know complexation

partner

• Need to generate multiple 3D

models of complex

• BSSE

• Relevance to physiological

media?

Calculate molecular

electrostatic properties

• No explicit reference to

complexation partner

• More appropriate to general

parameterisation

Minimised electrostatic potential has been shown to be an effective predictor of hydrogen 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

0V

0 1 2 3 4 5

r

Electrostatic potential as function of position for acceptor

V/k

Jm

ol-1

r/Å

Comparison of Vmin and pKa as predictors of logKb

logK

b

Vmin/(Hartree/electron) pKa

Heteroaromatic nitrogen in five and six-membered rings

Kenny JCS Perkin Trans 2 1994, 199-202

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

r

Donors: The Va(r) descriptor

Calculate electrostatic

potential (V) at this point

Va(r) as predictor of logKa

Sensitivity to distance from donor hydrogen

Va/(Hartree/electron) Va/(Hartree/electron)

log

Ka

log

Ka

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

Fluorine: A weak hydrogen bond acceptor

-0.122 -0.113 -0.071

-0.038

-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

-0.316

-0.315

-0.296

-0.295

Bioisosterism: Carboxylate & tetrazole

Kenny, JCIM, 2009, 49, 1234-1244

-0.262

-0.261

-0.268

-0.268

G

Do1

Do2

Ac1 Ac2

A

Do1 Do2

Ac1

Kenny, JCIM, 2009, 49, 1234-1244

DNA Base Isosteres: Acceptor & Donor Definitions

Watson-Crick Donor & Acceptor Electrostatic Potentials for

Adenine IsosteresV

min

(Ac1)

Va (Do1)

Kenny, JCIM, 2009, 49, 1234-1244

IsostereDuplex

stabilityDonor (Do1) Donor (Do2)

Acceptor

(Ac1)

reference 0.335 0.331 -0.086

- 0.329 0.325 -0.089

+ 0.340 0.336 -0.079

pred + 0.341 0.348Minimum not

located

Guanine bioisosteres & DNA duplex stability

Kenny, JCIM, 2009, 49, 1234-1244

+

+

+

Ternary complex

K1

K2

Quantifying the effect of complex formation

Kenny, JCIM, 2009, 49, 1234-1244

HO

H HO

H HO

H

H

OH

N

H

O

Effect of complex formation on predicted

hydrogen bond acidity of water

1.2

(~ Alcohol)

2.0

(~ Phenol)

2.8

(~ 4-CF3Phenol)

Kenny, JCIM, 2009, 49, 1234-1244

Polarity

NClogP ≤ 5 Acc ≤10; Don ≤5

An alternative view of the Rule of 5

Octanol/Water Alkane/Water

Octanol/water is not the only partitioning system

logPalk: Experimental challenges

• Many polar solutes are poorly soluble in alkane solvents

• Self-association

– Masks polarity

– Limits concentration at which measurements can be made.

– Need to vary concentration to demonstrate that it is not an issue

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


DlogP = 0.5

PSA = 48 Å2

DlogP = 4.3

PSA = 22 Å2

PSA is not predictive of hydrogen bond strength


1.0 1.1 0.8 1.3 1.7

0.8 1.5

Measured values of DlogP


1.6 1.1

DlogP

(corrected)

Vmin/(Hartree/electron)

DlogP

(corrected)

Vmin/(Hartree/electron)

N or ether OCarbonyl O

Prediction of contribution of acceptors to DlogP


DlogP = DlogP0 x exp(-kVmin)

logPhxdlogPoct

log

(Cbra

in/C

blo

od)

DlogP

Prediction of blood/brain partitioning

R2 = 0.66

RMSE = 0.54R2 = 0.82

RMSE = 0.39

R2 = 0.88

RMSE = 0.32


What is a hydrogen bond worth?

Cathepsin L binding site

Asaad et al, Bioorg. Med. Chem. Lett. 2009 , 19, 4280-4283

Cathepsin S

pIC50

Cathepsin L2

pIC50

Cathepsin L

pIC50

6.9 6.1 6.6

6.2 < 5 5.5

8.1 7.2 5.9

Cathepsin inhibition pIC50 values

Bethel et al, Bioorg. Med. Chem. Lett. 2009 , 19, 4622-4625

Hydrogen Bonding in the Design Context

• Biomolecular recognition occurs in buffered aqueous

media

– Binding of ligand to protein can be viewed as ‘exchange’ reaction

– Balanced hydrogen bonding characteristics required for optimal

interaction

– Non-local effects can be important

• Multiple contacts between protein and ligand

– Intermolecular hydrogen bonds in ligand-protein complex are

likely to be of less ideal geometry than hydrogen bonds between

protein or ligand and water (Molecular Complexity)

Some questions to finish

• How relevant are van der Waals radii to hydrogen

bonding?

• How physical are atom-centered charges?

• Why ignore the points where electrostatic potential is most

predictive of hydrogen bond strength when fitting atomic

charges to electrostatic potential?

• Is it possible to identify those atom types for which

polarisability treatment would be of most benefit?

Selected references

• Abraham (1993) Scales of Hydrogen-bonding: Their Construction and Application to Physicochemical and

Biochemical Processes. Chem. Soc. Rev. 22, 73-83. http://dx.doi.org/10.1039/CS9932200073

• Abraham et al (1989) Hydrogen bonding. Part 9. Solute proton-donor and proton-acceptor scales for use in

drug design. J. Chem. Soc. Perkin Trans. 2, 1989, 1355-1375. http://dx.doi.org/10.1039/P29890001355

• Laurence and Berthelot (2000) Observations on the strength of hydrogen bonding. Perspect. Drug. Discov.

Des. 18, 39-60. http://dx.doi.org/10.1023/A:1008743229409

• Laurence et al (2009): The pKBHX Database: Toward a Better Understanding of Hydrogen-Bond Basicity

for Medicinal Chemists. J. Med. Chem. 52, 4073-4086. http://dx.doi.org/10.1021/jm801331y

• Kenny (2009) Hydrogen Bonding, Electrostatic Potential and Molecular Design. J. Chem. Inf. Model. 2009,

49, 1234-1244. http://dx.doi.org/10.1021/ci9000234

• Kenny (1994) Prediction of hydrogen bond basicity from computed molecular electrostatic potential

properties. J. Chem. Soc. Perkin Trans. 2 1994, 199-202. http://dx.doi.org/10.1039/P29940000199

• Toulmin, Wood & Kenny (2008) Toward Prediction of Alkane/Water Partition Coefficients. J. Med. Chem.

51, 3720-3730. http://dx.doi.org/10.1021/jm701549s

hydrogen bonding and molecular design (euroqsar 2010)

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