Optimizing Target Interactions Chapter 13 Optimizing Target Interactions

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

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

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

Structure-activity relationships (SAR) HO O MORPHINE NMe MOR025.WAV HO

Structure-activity relationships (SAR) H3CO O CODEINE NMe MOR025.WAV HO ACTIVITY DROPS

Structure-activity relationships (SAR) HO O MORPHINE NMe MOR025.WAV HO

Structure-activity relationships (SAR) HO O 6-OXYMORPHINE NMe MOR025.WAV O ACTIVITY UNAFFECTED

Structure-activity relationships (SAR) Important groups for activity HO O MORPHINE NMe MOR025.WAV HO

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

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

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

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

SAR on 1o, 2o & 3o amines (RNH2, RNHR, R3N) Analogues of 1o & 2o amines Effect on binding CO2- Binding site No interaction N CH3 O R Amide analogue 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)

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

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

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

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

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

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 Fatty Barrier Prodrug Esterase Drug Prodrug Esterase Drug Ester masks polar groups Allows passage through fatty cell membranes

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

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

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

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

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

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 H-Bonding hindered X H steric shield C O Analogue CH3 No ionic bonding possible NHR2 binding site C O Analogue CH3 +

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

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)

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

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 Drug Analogue