1) The document summarizes an evaluation of methods for predicting hydrogen bond strength, including Peter Kenny's accurate but slow quantum mechanics (QM) approach and the faster but less accurate Cresset molecular modeling software. 2) Applying Kenny's QM approach to 9 kinase ligand cores, excellent correlations with potency were found except for two outliers, while Cresset captured trends but not substituent effects. 3) A combination of Kenny's QM predictions with Cresset screening was proposed to effectively optimize ligand hydrogen bonding for potency, with each method's strengths mitigating the other's weaknesses.

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
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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)
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4. Peter Kenny’s method
P. Kenny, EuroQSAR 2010
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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
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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
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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
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8. HB acceptors: Kenny JChemSoc94 results
Pearson r -0.98
Spearman rho -0.97
Vmin_Kenny94(kJ/mol)
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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
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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
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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
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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
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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
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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
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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)
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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
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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)
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18. Acknowledgements
• Cresset
 Mark Mackey
 Martin Slater
 Tim Cheeseright
 Andy Vinter
• Galapagos computational chemistry group
 Pieter Stouten
 Cornel Catana
 Nicolas Triballeau
 Miriam Lopez-Ramos
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