Hydrogen Bonding & Molecular Design
Peter Kenny(pwk.pub.2008@gmail.com)
Hydrogen
Bonding
Interactions between drug
molecules in crystal lattice
(Solubility, melting point
polymorphism, crystalli...
Neglect of hydrogen bond strength:
A recurring theme in medicinal chemistry
• Rule of 5
• Rule of 3
• Scoring functions fo...
Measuring hydrogen bond strength
Acceptors
Donors
pKHB logKb
logKa
(CH3CCl3)(CCl4)
Taft et al , JACS 1969, 91, 4801-4808
L...
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 0.8...
Modelling Hydrogen Bonding
Calculate energy of
complex
• Need to know complexation
partner
• Need to generate multiple 3D
...
bond basicity
 Plot of V/kJmol-1
against r/Å for pyridine on lone pair axis
showing electrostatic potential minimum 1.2Å...
Comparison of Vmin and pKa as predictors of logKb
logKb
Vmin/(Hartree/electron) pKa
Heteroaromatic nitrogen in five and si...
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...
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)
logK...
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
-...
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 Isosteres
Vmin(Ac1)
Va (Do1)
Kenny, JCIM, 2009, 49, 123...
Isostere
Duplex
stability
Donor (Do1) Donor (Do2)
Acceptor
(Ac1)
reference 0.335 0.331 -0.086
- 0.329 0.325 -0.089
+ 0.340...
+
+
+
Ternary complex
K1
K2
Quantifying the effect of complex formation
Kenny, JCIM, 2009, 49, 1234-1244
H
O
H H
O
H H
O
H
H
O
H
N
H
O
Effect of complex formation on predicted
hydrogen bond acidity of water
1.2
(~ Alcohol)
2.0
...
Polarity
N
ClogP ≤ 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 pol...
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
...
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. Che...
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 O
Carbonyl O
Prediction of ...
logPhxdlogPoct
log(Cbrain/Cblood)
DlogP
Prediction of blood/brain partitioning
R2 = 0.66
RMSE = 0.54
R2 = 0.82
RMSE = 0.39...
What is a hydrogen bond worth?
Cathepsin L inhibitors
Asaad et al, Bioorg. Med. Chem. Lett. 2009 , 19, 4280-4283
http://dx...
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 valu...
Hydrogen Bonding in the Design Context
• Biomolecular recognition occurs in buffered aqueous
media
– Binding of ligand to ...
Some questions to finish
(mainly of interest to computational chemists)
• How relevant are van der Waals radii to hydrogen...
Selected references
• Abraham (1993) Scales of Hydrogen-bonding: Their Construction and Application to Physicochemical and...
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Hydrogen bonding and molecular design (BrazMedChem 2010)

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These are the slides that I used at BrazMedChem 2010 in Ouro Preto and it is essentially the same presentation that I'd done a few weeks earlier at EuroQSAR.

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Hydrogen bonding and molecular design (BrazMedChem 2010)

  1. 1. Hydrogen Bonding & Molecular Design Peter Kenny(pwk.pub.2008@gmail.com)
  2. 2. 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)
  3. 3. 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) as molecular descriptor • Relationships between binding thermodynamic and buried polar/non-polar surface area
  4. 4. 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
  5. 5. 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
  6. 6. 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
  7. 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/År/Å r
  8. 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
  9. 9. 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
  10. 10. r Donors: The Va(r) descriptor Calculate electrostatic potential (V) at this point
  11. 11. 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
  12. 12. Fluorine: A weak hydrogen bond acceptor -0.122 -0.113 -0.071 -0.038
  13. 13. -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
  14. 14. -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
  15. 15. G Do1 Do2 Ac1 Ac2 A Do1 Do2 Ac1 Kenny, JCIM, 2009, 49, 1234-1244 DNA Base Isosteres: Acceptor & Donor Definitions
  16. 16. Watson-Crick Donor & Acceptor Electrostatic Potentials for Adenine Isosteres Vmin(Ac1) Va (Do1) Kenny, JCIM, 2009, 49, 1234-1244
  17. 17. Isostere Duplex stability Donor (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 0.348 Minimum not located Guanine bioisosteres & DNA duplex stability Kenny, JCIM, 2009, 49, 1234-1244
  18. 18. + + + Ternary complex K1 K2 Quantifying the effect of complex formation Kenny, JCIM, 2009, 49, 1234-1244
  19. 19. H O H H O H H O H H O H 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
  20. 20. Polarity N ClogP ≤ 5 Acc ≤10; Don ≤5 An alternative view of the Rule of 5
  21. 21. Octanol/Water Alkane/Water Octanol/water is not the only partitioning system
  22. 22. 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
  23. 23. 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
  24. 24. 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
  25. 25. 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
  26. 26. DlogP (corrected) Vmin/(Hartree/electron) DlogP (corrected) Vmin/(Hartree/electron) N or ether O Carbonyl O Prediction of contribution of acceptors to DlogP Toulmin et al, J. Med. Chem. 2008, 51, 3720-3730 DlogP = DlogP0 x exp(-kVmin)
  27. 27. logPhxdlogPoct log(Cbrain/Cblood) DlogP Prediction of blood/brain partitioning R2 = 0.66 RMSE = 0.54 R2 = 0.82 RMSE = 0.39 R2 = 0.88 RMSE = 0.32 Toulmin et al, J. Med. Chem. 2008, 51, 3720-3730
  28. 28. What is a hydrogen bond worth? Cathepsin L inhibitors Asaad et al, Bioorg. Med. Chem. Lett. 2009 , 19, 4280-4283 http://dx.doi.org/doi:10.1016/j.bmcl.2009.05.071 Bethel et al, Bioorg. Med. Chem. Lett. 2009 , 19, 4622-4625 http://dx.doi.org/doi:10.1016/j.bmcl.2009.06.090 pIC50 values: CatL: 8.7 CatB: 5.4 CatL2: 7.4 CatS: 6.7 pIC50 values: CatL: 7.9 CatB: 5.4 CatL2: 6.4 CatS: 6.1 pIC50 values: CatL: 8.7 CatB: 5.2 CatL2: 7.0 CatS: 7.2
  29. 29. 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
  30. 30. 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)
  31. 31. Some questions to finish (mainly of interest to computational chemists) • 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?
  32. 32. 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

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