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Hydrogen bond strength predictions:
could we do better?
 Raphaël GENEY, PhD
 Scientist, Computational Chemistry

 Cresset UGM
 22 September 2011


                                      © Copyright 2011 Galapagos NV
Background

• Motivation: answer recurrent chemist question to predict
  basicity of HB acceptor/acidity of HB donor, in order to correlate
  with affinity
• Quick overview of literature highlighted the methods of Peter
  Kenny (then at AstraZeneca) as simple and accurate for both
  HB acceptors and donors strength assessment
    method rigourously tested and sufficiently described to quickly reproduce




                                       2
Peter Kenny’s method
• Uses projected electrostatic field rather than two-body
  calculation
          avoids need to correct for Basis Set Superposition Error

• From HF/6-31G* minimized geometries
   HB acceptors (J. Chem. Soc. 1994, 2, 199-202)
       calculate electrostatic potential minimum along acceptor lone pair axis
       HF/6-31G* calculation in GAUSSIAN
   HB donors (J. Chem. Inf. Model. 2009, 49, 1234-1244)
       calculate electrostatic potential value 0.55 Å away from donor H in D-H
        direction
       B3LYP/6-31+G** is most predictive (GAUSSIAN)


                                         3
Peter Kenny’s method




      P. Kenny, EuroQSAR 2010
                      4
Implementing Kenny’s approach
From HF/6-31G* minimized geometries (PC GAMESS, aka Firefly)
• HB acceptors
   calculate electrostatic potential grid around acceptor atom
          ±2 Å around acceptor, 0.05 Å grid spacing (80^3=512 000 grid points!)
   HF/6-31G* calculation in PC GAMESS

• HB donors
   calculate electrostatic potential value 0.55 Å away from donor H in D-H
    direction
   B3LYP/6-31+G** calculation in PC GAMESS




                                       5
Experimental data
• HB strength quantified by measuring association constants
  for donor-acceptor complexes in nonpolar solvent
• All experimental data taken from Abraham et al, J. Chem.
  Soc. Perkin Trans. 2 1989, 10, 1355-1375


      Acceptors (UV)                        Donors (IR)
       logK                                  logK
HO       NO2   (CH3CCl3)                N
                                                 (CH3CCl3)
                                    O




                             6
HB donors: B3LYP/6-31+G** V(0.55) results


                                                      logK     exp   vs. V (0.55)
                                  3.5


                                   3

• Identical results to Kenny’s
                                  2.5

    only QM softwares differed
                                   2


                                  1.5


                                                                             in-house B3LYP/6-31+G**
                                   1
                                                                             Linear (in-house B3LYP/6-31+G**)
                                  0.5
                                                                                      R² = 0.9311

                                   0
                                        0.3   0.31   0.32   0.33     0.34   0.35    0.36     0.37      0.38




                                              7
HB acceptors: Kenny JChemSoc94 results




      Pearson r   -0.98
    Spearman rho -0.97

                          Vmin_Kenny94(kJ/mol)




                                         8
In-house HF/6-31G* GAMESS grid protocol




     Pearson r    -0.97
    Spearman rho -0.96

                           Vmin_HF(kJ/mol)


       Marginally worse results than published by Kenny
                                       9
HF/6-31G* from RM1 geometry




     Pearson r    -0.96
   Spearman rho -0.94


                            Vmin_HF(kJ/mol)1



      Much faster calculation, marginally worse correlations
                                        10
Cresset on Kenny JChemSoc94 dataset




     Pearson r     -0.53
    Spearman rho -0.64

                            Cresset_fieldsize



       Weak correlation of field size with logK
       Cresset seems unable to predict substituent effects
                                 11
Cresset FF minimization effect




      Geometry       HF     Cresset
      Pearson r     -0.57    -0.53
                                                      HF geometry
    Spearman rho    -0.65    -0.64                    Cresset minimized


                             Cresset_fieldsize




    A higher precision geometry only slightly improves correlations
                                                 12
New Cresset force field effect




     Force field    FF2       FF3
      Pearson r    -0.53    -0.55
                                                      Cresset FF3
    Spearman rho   -0.64    -0.64                     Cresset FF2


                             Cresset_fieldsize


         Systematic shift to larger Field Sizes observed with FF3
         Substituent effect remains unaccounted for
                                                 13
Example: kinase ligand scaffold hopping

• 9 topologically similar scaffolds synthesized in kinase project so far


• X-ray structure of ligand-kinase complex                                GK+1

  available for main compound series                               GK+2
                                                                                        GK
    mainly 1 point interaction with hinge GK+3 NH
    is potency related to HB acceptor strength?                   GK+3                      Ar
                                                            GK+4
                                                                                 Core
                                                                                  II


• Rather favorable case in Cresset FieldStere                       GK+5


    but FieldStere only returns overall similarity score
    no field point near donor nitrogen in some cases



                                               14
Example scaffold hopping
           QM results
        • Modified Kenny method applied on all 9 core acceptor N, with no sidechain present on cores
               excellent pIC50-Vmin correlation except for 2 cores in THP subseries
               in valinol subseries, core III is the only outlier
                          IC50 for core V in THP subseries might be wrong? Maybe a substituent effect?

               literature search indicates core III is basic enough to protonate at assay pH (pKa=6.9)!



                                                Core
                       Core                      II                                            Core
                         I                                                                       I
                                                              Core
                                                               IX                                                       Core
pIC50




                Core                     Core                                                                            II
                                                                     Core
                 III                      VII                         VI                 Core
                                                                                          III                            Core
                                                                                                                          IV

          O            X
                           N
                                  X                    Core                                    X
                                                                                                   N
                                                                                                          X
                                                                                                                              Core
                       X
                           Core
                                  X Ar                  V                           O          X
                                                                                                   Core
                                                                                                          X Ar
                                                                                                                               V
                  N         X                                                              N        X
                  THP                                                                    valinol

                                      Vmin (kJ/mol)                                                           Vmin (kJ/mol)
                                                                            15
Example scaffold hopping
            Cresset results

            • No exact correlation of field size with pIC50 observed
            • Cresset still partially picks up main trend and ranking


                                Core          Core                                         Core
                                  I            II                                            I

                                              Core
pIC50




                                   Core                                                                  Core
                 Core                          IX
                                    VII                                  Core                             II
                  III
                                                                          III                     Core
                                                                                                   IV
                                Core                                                                            Core
                                 VI                  Core
                     N                                                       N                                   V
        O        X
                     Core
                            X
                                                      V                  X
                                                                             Core
                                                                                    X
                 X      X Ar                                     O       X          X Ar
             N        X                                              N        X




                                 Field Size                                                Field Size
                                                            16
Summary
• Peter Kenny’s highly predictive QM HB strength prediction method identified and
  implemented for both HB acceptors and donors
    slow calculation for large systems
    I/O preparation currently labor intensive  low throuput


• Direct comparison of QM results with Cresset Field Sizes possible for HB acceptors
    Cresset captures general trend but fails to incorporate substituent effects
        could future XED force field releases take such effects into account?


• Combination of Cresset and the QM approach could prove effective for ligand HB
  profile optimization
    QM HB assessment method surprisingly predictive of ligand potency
    Cresset best alternative for high throughput searches, particularly when substituents are
     maintained (e.g. scaffold hopping in FieldStere)

                                                      17
Acknowledgements
• Cresset
   Mark Mackey
   Martin Slater
   Tim Cheeseright
   Andy Vinter

• Galapagos computational chemistry group
   Pieter Stouten
   Cornel Catana
   Nicolas Triballeau
   Miriam Lopez-Ramos

                           18

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Raphael Geney, Galapagos, H-bond strength predictions: Could we do better?

  • 1. Hydrogen bond strength predictions: could we do better? Raphaël GENEY, PhD Scientist, Computational Chemistry Cresset UGM 22 September 2011 © Copyright 2011 Galapagos NV
  • 2. Background • Motivation: answer recurrent chemist question to predict basicity of HB acceptor/acidity of HB donor, in order to correlate with affinity • Quick overview of literature highlighted the methods of Peter Kenny (then at AstraZeneca) as simple and accurate for both HB acceptors and donors strength assessment  method rigourously tested and sufficiently described to quickly reproduce 2
  • 3. Peter Kenny’s method • Uses projected electrostatic field rather than two-body calculation  avoids need to correct for Basis Set Superposition Error • From HF/6-31G* minimized geometries  HB acceptors (J. Chem. Soc. 1994, 2, 199-202)  calculate electrostatic potential minimum along acceptor lone pair axis  HF/6-31G* calculation in GAUSSIAN  HB donors (J. Chem. Inf. Model. 2009, 49, 1234-1244)  calculate electrostatic potential value 0.55 Å away from donor H in D-H direction  B3LYP/6-31+G** is most predictive (GAUSSIAN) 3
  • 4. Peter Kenny’s method P. Kenny, EuroQSAR 2010 4
  • 5. Implementing Kenny’s approach From HF/6-31G* minimized geometries (PC GAMESS, aka Firefly) • HB acceptors  calculate electrostatic potential grid around acceptor atom  ±2 Å around acceptor, 0.05 Å grid spacing (80^3=512 000 grid points!)  HF/6-31G* calculation in PC GAMESS • HB donors  calculate electrostatic potential value 0.55 Å away from donor H in D-H direction  B3LYP/6-31+G** calculation in PC GAMESS 5
  • 6. Experimental data • HB strength quantified by measuring association constants for donor-acceptor complexes in nonpolar solvent • All experimental data taken from Abraham et al, J. Chem. Soc. Perkin Trans. 2 1989, 10, 1355-1375 Acceptors (UV) Donors (IR) logK logK HO NO2 (CH3CCl3) N (CH3CCl3) O 6
  • 7. HB donors: B3LYP/6-31+G** V(0.55) results logK exp vs. V (0.55) 3.5 3 • Identical results to Kenny’s 2.5  only QM softwares differed 2 1.5 in-house B3LYP/6-31+G** 1 Linear (in-house B3LYP/6-31+G**) 0.5 R² = 0.9311 0 0.3 0.31 0.32 0.33 0.34 0.35 0.36 0.37 0.38 7
  • 8. HB acceptors: Kenny JChemSoc94 results Pearson r -0.98 Spearman rho -0.97 Vmin_Kenny94(kJ/mol) 8
  • 9. In-house HF/6-31G* GAMESS grid protocol Pearson r -0.97 Spearman rho -0.96 Vmin_HF(kJ/mol)  Marginally worse results than published by Kenny 9
  • 10. HF/6-31G* from RM1 geometry Pearson r -0.96 Spearman rho -0.94 Vmin_HF(kJ/mol)1  Much faster calculation, marginally worse correlations 10
  • 11. Cresset on Kenny JChemSoc94 dataset Pearson r -0.53 Spearman rho -0.64 Cresset_fieldsize  Weak correlation of field size with logK  Cresset seems unable to predict substituent effects 11
  • 12. Cresset FF minimization effect Geometry HF Cresset Pearson r -0.57 -0.53 HF geometry Spearman rho -0.65 -0.64 Cresset minimized Cresset_fieldsize  A higher precision geometry only slightly improves correlations 12
  • 13. New Cresset force field effect Force field FF2 FF3 Pearson r -0.53 -0.55 Cresset FF3 Spearman rho -0.64 -0.64 Cresset FF2 Cresset_fieldsize  Systematic shift to larger Field Sizes observed with FF3  Substituent effect remains unaccounted for 13
  • 14. Example: kinase ligand scaffold hopping • 9 topologically similar scaffolds synthesized in kinase project so far • X-ray structure of ligand-kinase complex GK+1 available for main compound series GK+2 GK  mainly 1 point interaction with hinge GK+3 NH  is potency related to HB acceptor strength? GK+3 Ar GK+4 Core II • Rather favorable case in Cresset FieldStere GK+5  but FieldStere only returns overall similarity score  no field point near donor nitrogen in some cases 14
  • 15. Example scaffold hopping QM results • Modified Kenny method applied on all 9 core acceptor N, with no sidechain present on cores  excellent pIC50-Vmin correlation except for 2 cores in THP subseries  in valinol subseries, core III is the only outlier  IC50 for core V in THP subseries might be wrong? Maybe a substituent effect?  literature search indicates core III is basic enough to protonate at assay pH (pKa=6.9)! Core Core II Core I I Core IX Core pIC50 Core Core II Core III VII VI Core III Core IV O X N X Core X N X Core X Core X Ar V O X Core X Ar V N X N X THP valinol Vmin (kJ/mol) Vmin (kJ/mol) 15
  • 16. Example scaffold hopping Cresset results • No exact correlation of field size with pIC50 observed • Cresset still partially picks up main trend and ranking Core Core Core I II I Core pIC50 Core Core Core IX VII Core II III III Core IV Core Core VI Core N N V O X Core X V X Core X X X Ar O X X Ar N X N X Field Size Field Size 16
  • 17. Summary • Peter Kenny’s highly predictive QM HB strength prediction method identified and implemented for both HB acceptors and donors  slow calculation for large systems  I/O preparation currently labor intensive  low throuput • Direct comparison of QM results with Cresset Field Sizes possible for HB acceptors  Cresset captures general trend but fails to incorporate substituent effects  could future XED force field releases take such effects into account? • Combination of Cresset and the QM approach could prove effective for ligand HB profile optimization  QM HB assessment method surprisingly predictive of ligand potency  Cresset best alternative for high throughput searches, particularly when substituents are maintained (e.g. scaffold hopping in FieldStere) 17
  • 18. Acknowledgements • Cresset  Mark Mackey  Martin Slater  Tim Cheeseright  Andy Vinter • Galapagos computational chemistry group  Pieter Stouten  Cornel Catana  Nicolas Triballeau  Miriam Lopez-Ramos 18