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Hydrogen bonding and molecular design (EuroQSAR 2010)

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These are the slides used for my EuroQSAR2012 harangue in Rhodes on Sept 21, 2010. The photograph in the title slide was taken in Asunción.

These are the slides used for my EuroQSAR2012 harangue in Rhodes on Sept 21, 2010. The photograph in the title slide was taken in Asunción.


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  • 1. Hydrogen Bonding & Molecular Design Peter Kenny (pwk.pub.2008@gmail.com)
  • 2. 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
  • 3. 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)
  • 4. 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
  • 5. 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
  • 6. 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
  • 7. 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
  • 8. 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/Å
  • 9. 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
  • 10. 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
  • 11. r Donors: The Va(r) descriptor Calculate electrostatic potential (V) at this point
  • 12. 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
  • 13. Fluorine: A weak hydrogen bond acceptor -0.122 -0.113 -0.071 -0.038
  • 14. -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
  • 15. -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
  • 16. G Do1 Do2 Ac1 Ac2 A Do1 Do2 Ac1 Kenny, JCIM, 2009, 49, 1234-1244 DNA Base Isosteres: Acceptor & Donor Definitions
  • 17. Watson-Crick Donor & Acceptor Electrostatic Potentials for Adenine Isosteres Vmin(Ac1) Va (Do1) Kenny, JCIM, 2009, 49, 1234-1244
  • 18. 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
  • 19. + + + Ternary complex K1 K2 Quantifying the effect of complex formation Kenny, JCIM, 2009, 49, 1234-1244
  • 20. 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
  • 21. Polarity N ClogP ≤ 5 Acc ≤10; Don ≤5 An alternative view of the Rule of 5
  • 22. Octanol/Water Alkane/Water Octanol/water is not the only partitioning system
  • 23. 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
  • 24. 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
  • 25. 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
  • 26. 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
  • 27. 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)
  • 28. 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
  • 29. What is a hydrogen bond worth? Cathepsin L binding site Asaad et al, Bioorg. Med. Chem. Lett. 2009 , 19, 4280-4283
  • 30. 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
  • 31. 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)
  • 32. 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?
  • 33. 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