© Copyright 2011 Galapagos NV

Hydrogen bond strength predictions: could we do better?

Raphaël GENEY, PhD Scientist, Computational Chemistry Cresset UGM 22 September 2011

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

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)

4

Peter Kenny’s method

P. Kenny, EuroQSAR 2010

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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

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

NO2

OH

Acceptors (UV)

(CH3CCl3)

logK

N

O

Donors (IR)

(CH3CCl3)

logK

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

• Identical results to Kenny’s

only QM softwares differed

R² = 0.9311

0

0.5

1

1.5

2

2.5

3

3.5

0.3 0.31 0.32 0.33 0.34 0.35 0.36 0.37 0.38

logK exp vs. V (0.55)

in-house B3LYP/6-31+G**

Linear (in-house B3LYP/6-31+G**)

8

Vmin_Kenny94(kJ/mol)

HB acceptors: Kenny JChemSoc94 results

Pearson r -0.98

Spearman rho -0.97

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Vmin_HF(kJ/mol)

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

Marginally worse results than published by Kenny

Pearson r -0.97

Spearman rho -0.96

10

HF/6-31G* from RM1 geometry

Much faster calculation, marginally worse correlations

Vmin_HF(kJ/mol)1

Pearson r -0.96

Spearman rho -0.94

11

Cresset_fieldsize

Cresset on Kenny JChemSoc94 dataset

Weak correlation of field size with logK

Cresset seems unable to predict substituent effects

Pearson r -0.53

Spearman rho -0.64

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Cresset_fieldsize

Cresset FF minimization effect

Geometry HF Cresset

Pearson r -0.57 -0.53

Spearman rho -0.65 -0.64

A higher precision geometry only slightly improves correlations

HF geometry Cresset minimized

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Cresset_fieldsize

New Cresset force field effect

Systematic shift to larger Field Sizes observed with FF3

Substituent effect remains unaccounted for

Cresset FF3 Cresset FF2

Force field FF2 FF3

Pearson r -0.53 -0.55

Spearman rho -0.64 -0.64

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Example: kinase ligand scaffold hopping

• 9 topologically similar scaffolds synthesized in kinase project so far

• X-ray structure of ligand-kinase complex available for main compound series

mainly 1 point interaction with hinge GK+3 NH

is potency related to HB acceptor strength?

• Rather favorable case in Cresset FieldStere

but FieldStere only returns overall similarity score

no field point near donor nitrogen in some cases

Ar Core II

GK

GK+1

GK+2

GK+3 GK+4

GK+5

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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 III

Core VII

Core V

Core II

Core VI Core

III

Core I

Core I

Core II

Core V

Core IV

Core IX

THP valinol

X

XX

NX

XArN

OCore

X

XX

NX

XArN

OCore

pIC

50

Vmin (kJ/mol) Vmin (kJ/mol)

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Example scaffold hopping Cresset results

• No exact correlation of field size with pIC50 observed

• Cresset still partially picks up main trend and ranking

Core III Core

III

Core I

Core VII

Core II

Core IX

Core VI Core

V

Core V

Core II

Core I

Core IV

pIC

50

Field Size Field Size

X

XX

NX

XArN

OCore

X

XX

NX

XArN

OCore

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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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Acknowledgements

• Cresset

Mark Mackey

Martin Slater

Tim Cheeseright

Andy Vinter

• Galapagos computational chemistry group

Pieter Stouten

Cornel Catana

Nicolas Triballeau

Miriam Lopez-Ramos