hydrogen bonding and molecular design (brazmedchem 2010)
DESCRIPTION
These are the slides that I used at BrazMedChem 2010 in Ouro Preto and it is essentially the same presentation that I'd done a few weeks earlier at EuroQSAR.TRANSCRIPT
Hydrogen Bonding & Molecular Design
Peter Kenny([email protected])
Hydrogen Bonding
Interactions between drug molecules in crystal lattice
(Solubility, melting point polymorphism, crystallinity)
Interactions between drug and water molecules
(Solubility, distribution, permeability, potency, toxicity,
efflux, metabolism)
Interactions between drug molecules & (anti)target(s) (Potency, toxicity, efflux , metabolism, distribution)
Hydrogen Bonding in Drug Discovery & Development
Interactions between water molecules
(Hydrophobic effect)
Neglect of hydrogen bond strength:A recurring theme in medicinal chemistry
• Rule of 5• Rule of 3• Scoring functions for virtual screening • Polar surface area (PSA) as molecular descriptor• Relationships between binding thermodynamic and
buried polar/non-polar surface area
Measuring hydrogen bond strength
Acceptors
Donors
pKHB logKb
logKa
OH F OH NO2 (CH3CCl3)(CCl4)
Taft et al , JACS 1969, 91, 4801-4808Laurence & Berthelot, Perspect. Drug. Discov. Des. 2000, 18, 39-60.
Abraham et al, JCS Perkin Trans 2 1989, 1355-1375
N
O
Me
(CH3CCl3)
Abraham et al, JCS Perkin Trans 2 1989, 1355-1375
logKb: Heteroaromatic nitrogen
Azines
pKa 5.22 9.70 2.24 1.23 0.65
logKb 2.52 3.54 2.53 1.67 1.46
Azoles
pKa 7.25 2.09 0.80 -2.03
logKb 3.68 2.22 1.67 1.06
Abraham et al, JCS Perkin Trans 2 1989, 1355-1375
N N
N
NN
N
N
N
N
N
N
NN
N
O
NO
Modelling Hydrogen Bonding
Calculate energy of complex
• Need to know complexation partner
• Need to generate multiple 3D models of complex
• BSSE• Relevance to physiological
media?
Calculate molecular electrostatic properties
• No explicit reference to complexation partner
• More appropriate to general parameterisation
Minimised electrostatic potential has been show n to be an effective predictor of hydrogen bond basicity
Plot of V/kJmol-1 against r/Å for pyridine on lone pair axis show ing electrostatic potential minimum 1.2Å from nitrogen
-300
-200
-100
0
V
0 1 2 3 4 5
r
Electrostatic potential as function of position for acceptor
V/k
Jmo
l-1
r/Å
N
r/Å
r
Comparison of Vmin and pKa as predictors of logKb
logK
b
Vmin/(Hartree/electron) pKa
Heteroaromatic nitrogen in five and six-membered rings
Kenny JCS Perkin Trans 2 1994, 199-202
1.01 1.16 0.94 0.40 0.06
2.63 1.53 2.50 1.89 1.82
2.39
Predicted logKb 2.64 1.68 2.51 1.90 2.50
Measured logKb 2.38 1.98 2.36 2.17 1.99
NN
N
Ph
SN
N
S
Me
NN
N
Ph
N NN
MeN
N
NN
Non-equivalent acceptors provide validation set
Kenny JCS Perkin Trans 2 1994, 199-202
r
Donors: The Va(r) descriptor
Calculate electrostatic potential (V) at this point
Va(r) as predictor of logKa
Sensitivity to distance from donor hydrogen
V a /(Hartree/electron) V a /(Hartree/electron)
logK
a
logK
a
r = 0.55 Å r = 1.20 Å
R2 = 0.65RMSE = 0.43
R2 = 0.93RMSE = 0.20
Kenny, JCIM, 2009, 49, 1234-1244
Fluorine: A weak hydrogen bond acceptor
-0.122 -0.113 -0.071
-0.038
-0.054
-0.086-0.091
-0.072
-0.104 -0.093
Hydrogen bonding of esters
Toulmin et al, J. Med. Chem. 2008, 51, 3720-3730
-0.316
-0.315
-0.296
-0.295
Bioisosterism: Carboxylate & tetrazole
Kenny, JCIM, 2009, 49, 1234-1244
-0.262
-0.261
-0.268
-0.268
G
Do1
Do2
Ac1 Ac2
A
Do1 Do2
Ac1
Kenny, JCIM, 2009, 49, 1234-1244
DNA Base Isosteres: Acceptor & Donor Definitions
Watson-Crick Donor & Acceptor Electrostatic Potentials for Adenine Isosteres
N
N
N
N
NH2
N N
N
N
NH2
N
N
N
NH2
Vm
in (
Ac1
)
Va (Do1)Kenny, JCIM, 2009, 49, 1234-1244
NN
N
NH2
N
N
N
N
NH2
N
NN
N
NH2
IsostereDuplex stability
Donor (Do1) Donor (Do2)Acceptor
(Ac1)
reference 0.335 0.331 -0.086
- 0.329 0.325 -0.089
+ 0.340 0.336 -0.079
pred + 0.341 0.348 Minimum not located
N
N
N
NH
O
NH2
O
N
NH
NH2N
O
N
NH
NH2
N
N
NH2
NH N
N
N
O
Guanine bioisosteres & DNA duplex stability
Kenny, JCIM, 2009, 49, 1234-1244
+
+
+
Ternary complex
K1
K2
Quantifying the effect of complex formation
Kenny, JCIM, 2009, 49, 1234-1244
HO
H HO
H HO
H
H
OH
N
H
O
Effect of complex formation on predicted hydrogen bond acidity of water
1.2
(~ Alcohol)
2.0
(~ Phenol)
2.8
(~ 4-CF3Phenol)
Kenny, JCIM, 2009, 49, 1234-1244
Polarity
NClogP ≤ 5 Acc ≤10; Don ≤5
An alternative view of the Rule of 5
Octanol/Water Alkane/Water
OH OH
OHOH
Octanol/water is not the only partitioning system
logPalk: Experimental challenges
• Many polar solutes are poorly soluble in alkane solvents
• Self-association – Masks polarity– Limits concentration at which measurements can be made.– Need to vary concentration to demonstrate that it is not an
issue
logPoct = 2.1
logPalk = 1.9
DlogP = 0.2
OMe
OH
N
O
logPoct = 1.5
logPalk = -0.8
DlogP = 2.3
logPoct = 2.5
logPalk = -1.8
DlogP = 4.3
Differences in octanol/water and alkane/water logP values reflect hydrogen bonding between solute and octanol
Toulmin et al, J. Med. Chem. 2008, 51, 3720-3730
N
O
NO O
DlogP = 0.5
PSA = 48 Å2
DlogP = 4.3
PSA = 22 Å2
PSA is not predictive of hydrogen bond strength
Toulmin et al, J. Med. Chem. 2008, 51, 3720-3730
N N
N
N
N
NN
N
O
O
MeN
N
O
Me
Me
N
S
O O O
S
O
N
1.0 1.1 0.8 1.3 1.7
0.8 1.5
Measured values of DlogP
Toulmin et al, J. Med. Chem. 2008, 51, 3720-3730
1.6 1.1
DlogP (corrected)
Vmin/(Hartree/electron)
DlogP (corrected)
Vmin/(Hartree/electron)
N or ether OCarbonyl O
Prediction of contribution of acceptors to DlogP
Toulmin et al, J. Med. Chem. 2008, 51, 3720-3730
DlogP = DlogP0 x exp(-kVmin)
logPhxd logPoct
log(
Cb
rain/C
blo
od)
DlogP
Prediction of blood/brain partitioning
R2 = 0.66 RMSE = 0.54
R2 = 0.82 RMSE = 0.39
R2 = 0.88 RMSE = 0.32
Toulmin et al, J. Med. Chem. 2008, 51, 3720-3730
What is a hydrogen bond worth?Cathepsin L inhibitors
Asaad et al, Bioorg. Med. Chem. Lett. 2009 , 19, 4280-4283http://dx.doi.org/doi:10.1016/j.bmcl.2009.05.071
Bethel et al, Bioorg. Med. Chem. Lett. 2009 , 19, 4622-4625 http://dx.doi.org/doi:10.1016/j.bmcl.2009.06.090
pIC50 values:CatL: 8.7 CatB: 5.4 CatL2: 7.4 CatS: 6.7
pIC50 values:CatL: 7.9 CatB: 5.4 CatL2: 6.4 CatS: 6.1
NHN
O
NH
O
R
O
N NNH2
pIC50 values: CatL: 8.7 CatB: 5.2 CatL2: 7.0 CatS: 7.2
Cl
NHN
O
NH
O
R
R
O
NH
O
NHN
N
R
O
NH
O
NHN
NN
Cathepsin S pIC50
Cathepsin L2 pIC50
Cathepsin LpIC50
6.9 6.1 6.6
6.2 < 5 5.5
8.1 7.2 5.9
Cathepsin inhibition pIC50 values
Bethel et al, Bioorg. Med. Chem. Lett. 2009 , 19, 4622-4625
Hydrogen Bonding in the Design Context
• Biomolecular recognition occurs in buffered aqueous media– Binding of ligand to protein can be viewed as ‘exchange’
reaction– Balanced hydrogen bonding characteristics required for
optimal interaction– Non-local effects can be important
• Multiple contacts between protein and ligand – Intermolecular hydrogen bonds in ligand-protein complex
are likely to be of less ideal geometry than hydrogen bonds between protein or ligand and water (Molecular Complexity)
Some questions to finish(mainly of interest to computational chemists)
• How relevant are van der Waals radii to hydrogen bonding?
• How physical are atom-centered charges?• Why ignore the points where electrostatic potential is
most predictive of hydrogen bond strength when fitting atomic charges to electrostatic potential?
• Is it possible to identify those atom types for which polarisability treatment would be of most benefit?
Selected references
• Abraham (1993) Scales of Hydrogen-bonding: Their Construction and Application to Physicochemical and Biochemical Processes. Chem. Soc. Rev. 22, 73-83. http://dx.doi.org/10.1039/CS9932200073
• Abraham et al (1989) Hydrogen bonding. Part 9. Solute proton-donor and proton-acceptor scales for use in drug design. J. Chem. Soc. Perkin Trans. 2, 1989, 1355-1375. http://dx.doi.org/10.1039/P29890001355
• Laurence and Berthelot (2000) Observations on the strength of hydrogen bonding. Perspect. Drug. Discov. Des. 18, 39-60. http://dx.doi.org/10.1023/A:1008743229409
• Laurence et al (2009): The pKBHX Database: Toward a Better Understanding of Hydrogen-Bond Basicity for Medicinal Chemists. J. Med. Chem. 52, 4073-4086. http://dx.doi.org/10.1021/jm801331y
• Kenny (2009) Hydrogen Bonding, Electrostatic Potential and Molecular Design . J. Chem. Inf. Model. 2009, 49, 1234-1244. http://dx.doi.org/10.1021/ci9000234
• Kenny (1994) Prediction of hydrogen bond basicity from computed molecular electrostatic potential properties. J. Chem. Soc. Perkin Trans. 2 1994, 199-202. http://dx.doi.org/10.1039/P29940000199
• Toulmin, Wood & Kenny (2008) Toward Prediction of Alkane/Water Partition Coefficients . J. Med. Chem. 51, 3720-3730. http://dx.doi.org/10.1021/jm701549s