Chapter 13

1. Chapter 13 Optimizing Target Interactions

2. Stages of drug design and development 1) Identify target disease 2) Identify drug target 3) Establish testing procedures 4) Find a lead compound 5) Structure-activity relationships (SAR) 6) Identify a pharmacophore 7) Drug design - optimizing target interactions 8) Drug design - optimizing pharmacokinetic properties 9) Toxicological and safety tests 10) Chemical development and production 11) Patenting and regulatory affairs 12) Clinical trials

3. Structure-activity relationships (SAR) Aim - Identify which functional groups are important for binding and/or activity Method • Alter, remove or mask a functional group • Test the analogue for activity • Conclusions depend on the method of testing • in vitro - tests for binding interactions with target • in vivo - tests for target binding interactions and/or pharmacokinetics • If in vitro activity drops, it implies group is important for binding • If in vivo activity unaffected, it implies group is not important

4. Structure-activity relationships (SAR) • Modifications may disrupt binding by electronic / steric effects • Easiest analogues to make are those made from lead compound • Possible modifications may depend on other groups present • Some analogues may have to be made by a full synthesis • (e.g. replacing an aromatic ring with a cyclohexane ring) • Allows identification of important groups involved in binding • Allows identification of the pharmacophore

5. Structure-activity relationships (SAR) HO MORPHINE O NMe HO

6. ACTIVITY DROPS Structure-activity relationships (SAR) H3CO CODEINE O NMe HO

7. Structure-activity relationships (SAR) HO MORPHINE O NMe HO

8. Structure-activity relationships (SAR) HO 6-OXYMORPHINE O NMe O ACTIVITY UNAFFECTED

9. Structure-activity relationships (SAR) Important groups for activity HO MORPHINE O NMe HO

10. HBD HBA Drug Drug H O O H X X H X= N or O Binding site Binding site Ether Ester Alkane SAR on alcohols Possible binding interactions Possible analogues

11. CH3 CH3 O O H X X X= N or O Ether analogue Ether analogue steric shield Binding site Binding site SAR on alcohols Possible effect of analogues on binding (e.g. ether) No interaction as HBD No interaction as HBA

12. HBD Drug Drug NH2R + + X X= N or O CO2- Binding site Binding site + H R3NH acts as a strong HBD N R2 SAR on 1o, 2o & 3o amines (RNH2, RNHR, R3N) Possible binding interactions if amine is ionized Ionic H-Bonding

13. HBA HBD Drug Drug H N N H X X R X= N or O Binding site Binding site R H SAR on 1o, 2o & 3o amines (RNH2, RNHR, R3N) Possible binding interactions for free base H-Bonding Note: 3o Amines are only able to act as HBA’s - no hydrogen available to act as HBD

14. CO2- Binding site O Amide analogue N CH3 R No interaction SAR on 1o, 2o & 3o amines (RNH2, RNHR, R3N) Analogues of 1o & 2o amines Effect on binding • Notes • 1o and 2o amines are converted to 2o and 3o amides respectively • Amides cannot ionize and so ionic bonding is not possible • An amide N is a poor HBA and so this eliminates HBA interactions • Steric effect of acyl group is likely to hinder NH acting as a HBD (2o amide)

15. SAR on 1o, 2o & 3o amines (RNH2, RNHR, R3N) Analogues of 3o amines containing a methyl substituent

16. Ionic bonding Induced dipole interactions d+ + + d- CO2- Binding site Binding site Drug Drug NR3 NR3 SAR on quaternary ammonium salts (R4N+) Possible binding interactions Analogues Full synthesis of 1o-3o amines and amides

17. Dipole-dipole interaction H-Bonding HBA Drug Drug O O H X Binding site (X= N or O) Binding site SAR on aldehydes and ketones Possible binding interactions Analogues

18. Alcohol analogue H H Binding site (X= N or O) X OH SAR on aldehydes and ketones Effect on binding Change in stereochemistry (planar to tetrahedral) May move oxygen out of range If still active, further reactions can be carried out on alcohol to establish importance of oxygen

19. SAR on esters Possible binding interactions H-bonding as HBA by either oxygen Analogues • Notes • Hydrolysis splits molecule and may lead to a loss of activity due to loss of other functional groups - only suitable for simple esters. • Hydrolysis leads to a dramatic increase in polarity which may influence ability of analogue to reach target if in vivo tests are used • Reduction to alcohol removes carbonyl group and can establish importance of the carbonyl oxygen, but reaction can be difficult to do if other reactive functional groups are present

20. Prodrug Fatty Barrier Drug Esterase Prodrug Esterase Drug SAR on esters • Notes • Esters are usually hydrolysed by esterases in the blood • Esters are more likely to be important for pharmacokinetic reasons i.e. acting as prodrugs Ester masks polar groups Allows passage through fatty cell membranes

21. Drug H N O HBD HBA R H X Binding site (X= N or O) Binding site (X= N or O) O Drug R N H X SAR on amides Possible binding interactions • Notes • The nitrogen of an amide cannot act as a HBA - lone pair interacts with neighboringcarbonyl group • Tertiary amides unable to act as HBD’s

22. SAR on amides Analogues • Notes • Hydrolysis splits molecule and may lead to loss of activity due to loss of other functional groups - only suitable for simple amides. • Hydrolysis leads to dramatic increase in polarity which may affect ability of analogue to reach target if in vivo tests are done • Reduction to amine removes carbonyl group and can establish importance of the carbonyl oxygen, but reaction may be difficult to do if other reactive groups are present

23. O R N CH3 H Analogue X Analogue No binding as HBD Binding of O as HBA hindered steric shield O R N CH3 binding site X SAR on amides Analogues • N-Methylation prevents HBD interaction and may introduce a steric effect that prevents an HBA interaction

24. Drug O Drug C HBA HBD HBA O H O C H H H O X X Binding site (X= N or O) Binding site (X= N or O) Binding site (X= N or O) Drug O C X O H SAR on carboxylic acids Possible binding interactions as free acid

25. Drug Drug O O HBA Ionic bonding C C + O O H X Binding site (X= N or O) Binding site (X= N or O) - - NHR2 SAR on carboxylic acids Possible binding interactions as carboxylate ion • Notes • Charged oxygen atoms are strong HBA’s • Group can interact by ionic and hydrogen bonding at the same time

26. + H X No ionic bonding possible H-Bonding hindered Analogue Analogue NHR2 O O C C steric shield O O CH3 CH3 binding site SAR on carboxylic acids Possible analogues • Possible effects • Reduction removes carbonyl oxygen as potential HBA and prevents ionization • Esterification prevents ionization, HBD interactions and may hinder HBA by a steric effect

27. Analogue Analogue binding site binding site ‘Buffers’ R hydrophobic region R hydrophobic pocket H H H H SAR on aromatic rings and alkenes Possible effects on binding No fit

28. Miscellaneous functional groups in drugs • Acid chlorides - too reactive to be of use • Acid anhydrides - too reactive to be of use • Alkyl halides - present in anticancer drugs -react with nucleophiles in DNA • Aryl halides - commonly present. Not usually involved in binding directly • Nitro groups - sometimes present but often toxic • Alkynes - sometimes present, but not usually important in binding interactions • Thiols - present in some drugs as important binding group to transition metals (e.g. Zn in zinc metalloproteinases) • Nitriles - present in some drugs but rarely involved in binding • Notes • Functional groups may be important for electronic reasons (e.g. nitro, cyano, aryl halides) • Functional groups may be important for steric reasons • (e.g. alkynes)

29. Drug Drug van der Waals interactions binding site binding site CH3 H3C CH3 hydrophobic ‘pocket’ hydrophobic slot CH3 SAR of alkyl groups Possible interactions

30. Drug Drug Drug Analogue Analogue Analogue SAR of alkyl groups Analogues Easiest alkyl groups to vary are substituents on heteroatoms Vary length and bulk of alkyl group to test space available