Classical Electrostatics and Drug Design: Enumeration and Evaluation of Isosteric Analogs

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Classical Electrostatics and Drug Design
Enumeration and Evaluation of Isosteric Analogs

• Roger Sayle, Bob Tolbert, Andrew Grant and
  Anthony Nicholls
• OpenEye Scientific Software,
• Santa Fe, New Mexico

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Motivation Docking is Difficult

• Protein Flexibility
• Conformational Strain
• VdW Clash Resolution
• Entropic Effects
• Temperature Pressure

• Hydrogen Bonding
• Hydrophobic Effect
• Desolvation Terms
• Tautomerism
• pKa/Protonation State

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Cheating Docking Isosteres

• Isosteres are compounds with the same shape.
• For this talk, an isostere has the same heavy
  atom topology and non-terminal hybridizaton state
  (geometry).
• Isosteres are more likely to adopt the same
  binding mode than non-isosteric compounds.
• Given a bound ligand-protein complex crystal
  structure, we can extrapolate isosteres with more
  confidence.
• QSAR works well within compound series.

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Cheating is what were good at!

• All remaining docking terms are electrostatic.
• Use state-of-the-art partial charging methods and
  continuum solvent electrostatics models.
• Continuous dielectric Poisson-Boltmann.
• Modern bond-charge increment partial charges.
• Efficient and realistic isostere/state
  generation.
• Dramatic simplification in electrostatic
  contribution evaluation.
• WABE GIMBLE

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WABE Crosswords for chemists
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Solving the Jigsaw Puzzle

• Wabe reads a molecule database as a training set.
• An unique atom type forms a piece, consisting of
  atomic number, formal charge, implicit hydrogen
  count, heavy degree and valence.
• The pieces edges are formed by the atom types of
  its immediate neighbors.
• A piece may be substituted into the puzzle if
  its heavy degree and hybridization match the
  template.
• Different training sets can used to tailor the
  acceptable results actives, non-toxic, known
  chemistry, available.

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Example WABE solutions
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Electrostatics in Water
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Electrostatics in an Active Site
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Perfect Charges
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Tidor Perfect Charges
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Gimble

• Using Tidors formulation of the matrix its
  possible to calculate electrostatic binding
  energies orders of magnitude faster than full
  Poisson-Boltzmann calculations.
• Full PB times (zap_bind)
• 1320 mols 54m44 2.48 s/mol
• Gimble times
• 1320 mols 1m34s ltlt 0.07 s/mol

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Gimble Approximation Accuracy
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Really CheatingKnowing the answer in advance

• Methotrexate/DHFR

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Examples of Ring Substitutions
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The Best and the Worst
1199

• Better then methotrexate (221/1320)!

1047
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Specifics
Literature Charged WABE Monday Morning, 8am
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Specifics
Literature Doesnt Matter WABE Effect is small
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Specifics
Literature Essential WABE Essential
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Specifics
Literature Non-Essential WABE Non-Essential
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Specifics
Literature C better than N WABE Mais Oui!
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Learning from CheatingWhen you didnt really
know the correct answer.
Exptl IC50 3.1µM
Exptl IC50 0.125µM

• Hansch et al., J. Med. Chem., 20, 96-102, 1977.
• Piper et al., J. Med. Chem., 29, 1080-1086, 1986.
• Graffner-Nordberg et al., J. Med. Chem., 43,
  3852-3861, 2000.

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But does it scale?
33,250 analogues, Gimble takes 2m41s, gt 200
mols/s
30609
26192
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Perhaps we were lucky?
Astra Zeneca M532121/p56 Lck Kinase
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X-ray Structure of Lck-M532121
1.5Å crystal complex (R19.7, Rfree21.7)
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We didnt know we could cheat

• Discovery of 2-Phenylamino-imidazo4,5-hisoquinol
  in-9-ones A New Class of Inhibitors of Lck
  Kinase,
• R. Snow, M. Cardozo, T. Morwick, C. Busacca, Y.
  Dong, R. Eckner, S. Jacober, S. Jakes, S.
  Kapadia, S. Lukas, M. Panzenbeck, G. Peet, J.
  Peterson, A. Prokopowicz, R. Sellati, R. Tolbert,
  M. Tschantz and N. Moss.
• J. Med Chem. 2002, 45, 3394.

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Experimental Assay Data
Ureas ? Thioureas lt Guanidines CH3/Cl lt CH3/CH3 ?
Cl/Cl lt F/F
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Gimble Scores
Ureas ? Thioureas lt Guanidines CH3/Cl lt CH3/CH3 ?
Cl/Cl lt F/F
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1,792,000 compounds later...
Fluoro/Amino _at_2 Chloro/Methyl _at_3 Thiazinanium
_at_4 Methoxy _at_5 Oxazinanium _at_10 1,5-Naphthyridine
_at_13 Thiourea _at_15 Quinazoline _at_71 Urea _at_82
AZ Thiourea _at_360 AZ Urea _at_535
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The Timms Effect
Gimble (PB Electrostatics) picks up the critical
SAR of the solubilizing group thats pointing
into solvent.
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What worked and what didnt.

• MMFF94 charges perform significantly better than
  Marsilli-Gasteiger charges.
• Explicit hydrogens are important, but their
  placement isnt critical.
• Implicit hydrogens and united atom partial
  charges are sufficient to identify formal charge
  state, i.e. acid/base protonation, but not to
  distinguish between functional groups.

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Improvements in Partial Charging
Similar technological advances in
electrostatics e.g. smoothed dielectric boundary
methods (Zap)
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Conclusions

• Residual problems with radii differences.
• Medicinal chemistry from first principles
  physics.
• The technical problems with docking may still be
  with posing rather than scoring.
• A need for different smooth posing functions
  vs. accurate scoring functions?

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Acknowledgements

• Anthony, Bob and Geoff.
• Andrew Grant at AZ.
• Astra Zeneca.
• HP, IBM and SGI
• Lewis Carroll

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Bibliography

• Lewis Carroll, Through the Looking Glass.
• Lee-Peng Lee and Bruce Tidor, Optimization of
  electrostatic binding free energy, J. Chem.
  Phys., 106 (21), 8681-8690, June 1997.
• Erik Kangas and Bruce Tidor, Electrostatic
  Complementarity at Ligand Binding Sites
  Application to Chorismate Mutase, J. Phys. Chem.
  B., 105, 880-888, 2001.
• C. Hansch, J.Y. Fukunaga, P.Y.C. Jow and J.B.
  Hynes, Quantitative Structure-Activity
  Relationships of Antimalarial and Dihydrofolate
  Reductase Inhibition by Quinazolines and
  5-Substituted Benzyl-2,4-diaminopyrimidines, J.
  Med. Chem., 20 (1), 96-102, 1977.
• M. Gaffer-Nordberg et al., Computational
  Predictions of Binding Affinities to
  Dihydrofolate Reductase Synthesis and Biological
  Evaluation of Methotrexate Analogues, J. Med.
  Chem., 43 (21), 3852-3861, 2000.