Post on 02-Jul-2015
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Hydrogen Bonding & Molecular Design
Peter Kenny
(pwk.pub.2008@gmail.com)
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)
Abraham et al, JCS Perkin Trans 2 1989, 1355-1375
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
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
Toulmin et al, J. Med. Chem. 2008, 51, 3720-3730
DlogP = 0.5
PSA = 48 Å2
DlogP = 4.3
PSA = 22 Å2
PSA is not predictive of hydrogen bond strength
Toulmin et al, J. Med. Chem. 2008, 51, 3720-3730
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
DlogP
(corrected)
Vmin/(Hartree/electron)
DlogP
(corrected)
Vmin/(Hartree/electron)
N or ether OCarbonyl O
Prediction of contribution of acceptors to DlogP
Toulmin et al, J. Med. Chem. 2008, 51, 3720-3730
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
Toulmin et al, J. Med. Chem. 2008, 51, 3720-3730
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