Alkane/water partition coefficients and hydrogen bonding. Peter Kenny

Transcription

1 Alkane/water partition coefficients and hydrogen bonding Peter Kenny

2 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) Relationships between thermodynamic properties and buried polar & non-polar surface area

3 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 ,

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

5 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

6 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 r r/å

7 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 ,

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

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

10 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,

11 Fluorine: A weak hydrogen bond acceptor

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

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

14 Effect of complex formation on V min Toulmin et al, J. Med. Chem. 2008, 51,

15 Effect of complex formation on predicted logk a 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,

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

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

18 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

19 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,

20 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,

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

22 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,

23 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,

24 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,