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


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Cresset UGM, Cambridge,UK, Sept 2011. Raphael Geney, Presentation.

Cresset UGM, Cambridge,UK, Sept 2011. Raphael Geney, Presentation.

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  • 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 approachFrom 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 logKHO 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 CorepIC50 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 CorepIC50 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