DRUG DESIGN: OPTIMIZING TARGET INTERACTIONS Patrick An Introduction to Medicinal Chemistry 3/e Chapter 10 DRUG DESIGN: OPTIMIZING TARGET INTERACTIONS Part 1: Section 10.1 (SAR)

Contents Part 1: Section 10.1 (SAR) 1. Introduction to drug design & development 2. Structure Activity Relationships (SAR) (2 slides) 2.1. SAR on Alcohols (2 slides) 2.2. SAR on 1o, 2o & 3o Amines (RNH2, RNHR, R3N) (4 slides) 2.3. SAR on Quaternary Ammonium Salts (R4N+) 2.4. SAR on Aldehydes and Ketones (2 slides) 2.5. SAR on Esters (2 slides) 2.6. SAR on Amides (3 slides) 2.7. SAR on Carboxylic Acids (3 slides) 2.8. SAR on Aromatic Rings and Alkenes (2 slides) 2.9. Miscellaneous Functional Groups in Drugs 2.10. SAR of Alkyl Groups (2 slides) [26 slides]

1. Introduction to drug design & development Stages 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- optimising target interactions 8) Drug design - optimising pharmacokinetic properties 9) Toxicological and safety tests 10) Chemical development and production 11) Patenting and regulatory affairs 12) Clinical trials

2. 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

2. Structure Activity Relationships (SAR) NOTES ON ANALOGUES 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

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

2.1 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

2.2 SAR on 1o, 2o & 3o Amines (RNH2, RNHR, R3N) Possible binding interactions if amine is ionised 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

2.2 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

2.2 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 1o and 2o amines are converted to 2o and 3o amides respectively Amides cannot ionise 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)

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

2.3 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

2.4 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

2.4 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

2.5 SAR on Esters Possible binding interactions H-bonding as HBA by either oxygen Analogues 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 labile functional groups are present

2.5 SAR on Esters 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 masking polar groups allowing passage through fatty cell membranes

2.6 SAR on Amides Possible binding interactions 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 The nitrogen of an amide cannot act as a HBA - lone pair interacts with neighbouring carbonyl group Tertiary amides unable to act as HBD’s

2.6 SAR on Amides Analogues 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 labile groups are present

2.6 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

2.7 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

2.7 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 + Charged oxygen atoms are strong HBA’s Group could interact both as an ion and as a HBA at the same time

2.7 SAR on Carboxylic Acids Possible analogues Possible effects Reduction removes carbonyl oxygen as potential HBA and prevents ionisation Esterification prevents ionisation, 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 +

2.8 SAR on Aromatic Rings and Alkenes Possible binding interactions Drug Drug R binding site binding site vdw hydrophobic pocket hydrophobic region vdw Possible analogues

2.8 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

2.9 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 to form covalent bonds with nucleophiles in target 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 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)

2.10 SAR of Alkyl Groups Possible interactions Drug CH3 Drug CH3 H3C hydrophobic slot binding site binding site hydrophobic ‘pocket’ van der Waals interactions

2.10 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