Hydrogen Bonding & Molecular Design Peter

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1 Hydrogen Bonding & Molecular Design Peter

2 Hydrogen Bonding in Drug Discovery & Development Interactions between drug and water molecules (Solubility, distribution, permeability, potency, toxicity, efflux, metabolism) Interactions between drug molecules in crystal lattice (Solubility, melting point polymorphism, crystallinity) Hydrogen Bonding Interactions between drug molecules & (anti)target(s) (Potency, toxicity, efflux, metabolism, distribution) Interactions between water molecules (Hydrophobic effect)

3 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

4 Measuring hydrogen bond strength Acceptors pk HB logk b (CCl 4 ) (CH 3 CCl 3 ) Taft et al, JACS 1969, 91, Laurence & Berthelot, Perspect. Drug. Discov. Des. 2000, 18, Abraham et al, JCS Perkin Trans , Donors logk a (CH 3 CCl 3 ) Abraham et al, JCS Perkin Trans ,

5 logk b : Heteroaromatic nitrogen Azines pka logk b Azoles pka logk b Abraham et al, JCS Perkin Trans ,

6 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

7 bond basicity Electrostatic potential as function of position for acceptor Plot of V/kJmol -1 against r/å for pyridine on lone pair axis showing electrostatic potential minimum 1.2Å from nitrogen V/kJmol -1 V -200 r r r/å

8 logk b Comparison of V min and pk a as predictors of logk b V min /(Hartree/electron) pk a Heteroaromatic nitrogen in five and six-membered rings Kenny JCS Perkin Trans ,

9 Non-equivalent acceptors provide validation set Predicted logk b Measured logk b Kenny JCS Perkin Trans ,

10 Donors: The V a (r) descriptor r Calculate electrostatic potential (V) at this point

11 V a (r) as predictor of logk a Sensitivity to distance from donor hydrogen r = 0.55 Å r = 1.20 Å logk a logk a V a /(Hartree/electron) V a /(Hartree/electron) R 2 = 0.93 RMSE = 0.20 R 2 = 0.65 RMSE = 0.43 Kenny, JCIM, 2009, 49,

12 Fluorine: A weak hydrogen bond acceptor

13 Hydrogen bonding of esters Toulmin et al, J. Med. Chem. 2008, 51,

14 Bioisosterism: Carboxylate & tetrazole Kenny, JCIM, 2009, 49,

15 DNA Base Isosteres: Acceptor & Donor Definitions Do1 Do2 Ac1 Ac2 Ac1 Do2 Do1 A G Kenny, JCIM, 2009, 49,

16 V min (Ac1) Watson-Crick Donor & Acceptor Electrostatic Potentials for Adenine Isosteres V a (Do1) Kenny, JCIM, 2009, 49,

17 Guanine bioisosteres & DNA duplex stability Isostere Duplex stability Donor (Do1) Donor (Do2) Acceptor (Ac1) reference pred Minimum not located Kenny, JCIM, 2009, 49,

18 Quantifying the effect of complex formation + K 1 Ternary complex + K 2 + Kenny, JCIM, 2009, 49,

19 Effect of complex formation on predicted hydrogen bond acidity of water 1.2 (~ Alcohol) 2.0 (~ Phenol) 2.8 (~ 4-CF 3 Phenol) H O H H O H H O H H H H O N O Kenny, JCIM, 2009, 49,

20 An alternative view of the Rule of 5 N ClogP 5 Acc 10; Don 5 Polarity

21 Octanol/water is not the only partitioning system Octanol/Water Alkane/Water

22 logp alk : 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

23 Differences in octanol/water and alkane/water logp values reflect hydrogen bonding between solute and octanol logp oct = 2.1 logp alk = 1.9 DlogP = 0.2 logp oct = 1.5 logp alk = -0.8 DlogP = 2.3 logp oct = 2.5 logp alk = -1.8 DlogP = 4.3 Toulmin et al, J. Med. Chem. 2008, 51,

24 PSA is not predictive of hydrogen bond strength DlogP = 0.5 PSA = 48 Å 2 DlogP = 4.3 PSA = 22 Å 2 Toulmin et al, J. Med. Chem. 2008, 51,

25 Measured values of DlogP Toulmin et al, J. Med. Chem. 2008, 51,

26 Prediction of contribution of acceptors to DlogP DlogP (corrected) N or ether O DlogP (corrected) Carbonyl O V min /(Hartree/electron) V min /(Hartree/electron) DlogP = DlogP 0 x exp(-kv min ) Toulmin et al, J. Med. Chem. 2008, 51,

27 log(c brain /C blood ) Prediction of blood/brain partitioning R 2 = 0.66 RMSE = 0.54 R 2 = 0.82 RMSE = 0.39 R 2 = 0.88 RMSE = 0.32 logp oct logp hxd DlogP Toulmin et al, J. Med. Chem. 2008, 51,

28 What is a hydrogen bond worth? Cathepsin L inhibitors pic 50 values: CatL: 7.9 CatB: 5.4 CatL2: 6.4 CatS: 6.1 pic 50 values: CatL: 8.7 CatB: 5.4 CatL2: 7.4 CatS: 6.7 Asaad et al, Bioorg. Med. Chem. Lett. 2009, 19, Bethel et al, Bioorg. Med. Chem. Lett. 2009, 19, pic 50 values: CatL: 8.7 CatB: 5.2 CatL2: 7.0 CatS: 7.2

29 Cathepsin inhibition pic 50 values Cathepsin S pic 50 Cathepsin L2 pic 50 Cathepsin L pic < Bethel et al, Bioorg. Med. Chem. Lett. 2009, 19,

30 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)

31 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?

32 Selected references Abraham (1993) Scales of Hydrogen-bonding: Their Construction and Application to Physicochemical and Biochemical Processes. Chem. Soc. Rev. 22, 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, Laurence and Berthelot (2000) Observations on the strength of hydrogen bonding. Perspect. Drug. Discov. Des. 18, Laurence et al (2009): The pk BHX Database: Toward a Better Understanding of Hydrogen-Bond Basicity for Medicinal Chemists. J. Med. Chem. 52, Kenny (2009) Hydrogen Bonding, Electrostatic Potential and Molecular Design. J. Chem. Inf. Model. 2009, 49, Kenny (1994) Prediction of hydrogen bond basicity from computed molecular electrostatic potential properties. J. Chem. Soc. Perkin Trans , Toulmin, Wood & Kenny (2008) Toward Prediction of Alkane/Water Partition Coefficients. J. Med. Chem. 51,

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