Lecture 2

Question 1

Drug + Receptor Interactions

Answer 1

Simplified: “Lock & Key,” drug interlocks with receptor to exert therapeutic effect

Complex: Drug contains interacting groups held in place by a scaffold to bind to receptor

Question 2

Functional Groups + Scaffolds

Answer 2

• Scaffolds hold chemical in 3D space
• Interacting groups interact with receptor
• Sometimes groups are both scaffold and an interacting groups (EX: phenyl = hydrophobic interactor and a scaffold holding phenolic -OH at right distance from aliphatic -OH)

Question 3

Alkane

Answer 3

• single bonded C & H
• flexible (rotates around C-C bond)
• Hydrophobic

Question 4

Alkane Properties

Answer 4

Solubility- hydrophobic, so soluble in lipids, not water
Interactions- hydrophobic bond
Ionization states- none at biological pH
Chemical stability- very stable
Biological Reactivity- broadly unreactive, oxidized by P450
Uses in drug structures- very common, but not only scaffold
How common- very

Question 5

Alkene

Answer 5

C=C

• no rotation around double bond
• cis and trans isomers

Question 6

Alkene Properties

Answer 6

Chemical stability susceptible to oxidation
Uses in drug structures- scaffold & interacting group (polyene antifungals)
How common- moderate

Properties not included are the same as alkane

Question 7

Alkyne & Properties

Answer 7

-Triple C-C bond

Chemical stability less susceptible to oxidation
Biological Reactivity- often used to inhibit P450 through reactive intermediates
Uses in drug structures- scaffold & interacting group
How common- rare

Question 8

Cycloalkanes

Answer 8

• relatively flexible (boat and chair)
• RARE except in natural products
• All other properties are the same as acyclic alkanes

Question 9

Aromatics

Answer 9

• Hydrophobic (unless heterocyclic)

- Totally flat and no chirality

Question 10

Aromatic Properties

Answer 10

Solubility- hydrophobic, so soluble in lipids, not water
Interactions- hydrophobic bond
Ionization states- none at biological pH
Chemical stability- stable
Biological Reactivity- broadly unreactive, oxidized by P450 occasionally
Uses in drug structures- scaffold & interacting group
How common- exceedingly common

Question 11

Scaffold/Interactors: Heterocycles

Answer 11

• Both scaffold and interacting groups, very common as high atom efficiency
• Properties - similar to linear analogs
• Except when aromatics, pKa is usually very similar
• Exceedingly common, found in almost ALL drugs

Question 12

Halocarbons

Answer 12

Hydrogen of a hydrocarbon bond replaced by a halogen

• Usually interacting groups (aromatic Br, I, Cl)
• Replacement of metabolic susceptible H by F

Question 13

2-trifluoromethyl

Answer 13

• Powerful effects on acidity/bascity of groups
• Effects solubility, bioavailability, and metabolic stability
• Adding to a compound greatly helps solubility of carbon

Question 14

Hydroxyl (Alcohol)

Answer 14

• An oxygen single-bonded to a carbon
• Other valence site of O binds a H
• Can be primary, secondary, tertiary, or phenolic

Question 15

Hydroxyl Properties

Answer 15

Solubility- hydrophilic – promotes water solubility
Interactions- hydrogen bond
Ionization states- none at biological pH (except 1% -ve or so for phenols)
Chemical stability stable, but can be oxidized
Biological Reactivity- easily oxidized by P450, often site of Phase 2 metabolism
Uses in drug structures- hydrogen bond donor/acceptor: ↑H2O solubility
How common- very
Prodruggability easy conversion to ester

Question 16

Halocarbon Properties

Answer 16

Solubility- aromatic I, Br & Cl hydrophobic
but aliphatic F and especially trifluoromethyl quite
polar Interactions- depends, usually hydrophobic, some H bonding (esp F)
Ionization states- none at biological pH
Chemical stability stable (but not aliphatic Cl, Br, I)
Biological Reactivity- broadly unreactive, especially fluoro
Uses in drug structures- interacting group
How common- common

Question 17

Carbonyl

Answer 17

• Oxygen double bonded to carbon
• If carbon is primary = aldehyde
• If carbon is secondary = ketone

Question 18

Carbonyl Properties

Answer 18

Solubility- weakly hydrophillic
Interactions- hydrogen bond
Ionization states- none at biological pH
Chemical stability Unstable, reacts with amines and other groups, can be oxidized
Biological Reactivity- oxidized and reduced, reacts with proteins, DNA etc.
Uses in drug structures- H bond acceptor, reactive group.
How common- rare: DNA and protein reactivity makes it a liability
Prodruggability- not easy.

Question 19

Carboxylic Acid

Answer 19

• RC(O)OH
• Not simple combination of ketone and alcohol
• Special properties of its own

Question 20

Carboxylic Acid Properties

Answer 20

Solubility- very hydrophillic
Interactions- both ionic and hydrogen bond, depending on pH
Ionization states- pKa 3-6 so >99% -ve at pH7, neutral at pH 1 this drives differential ionization in stomach (pH 3- 5) vs intestine (pH 6-7.5) and can be important
Chemical stability- very stable
Biological Reactivity- site of phase 2 metabolism
Uses in drug structures- ionic bonder, H bond acceptor & donor: ↑H2O solubility
How common- relatively common
Prodruggability- easy conversion to ester or amide

Question 21

Ester

Answer 21

• RO-C=O

- Formed by reversible dehydration reaction with carboxylic acid and alcohol

Question 22

Ester Properties

Answer 22

Solubility- very hydrophobic
Interactions- hydrogen bond acceptor
Ionization states- none
Chemical stability- Stable unless water present, if not dry hydrolysis occurs
Biological Reactivity- usually converted to acid and alcohol by esterase enzymes
Uses in drug structures- To “hide” polar groups as prodrug to increase permeability across membranes
How common- quite common
Prodruggability- it IS a prodrug form of alcohol & acid

Question 23

Ether

Answer 23

• R-O-R’
• Oxygen linking two carbons
• Carbons can be aromatic or aliphatic

Question 24

Ethers Properties

Answer 24

Chemical stability very stable
Biological Reactivity- often converted to alcohol by– O demethylation, by P450 enzymes
Uses in drug structures- hydrophobic H bond acceptor
How common- not so much
Prodruggability- none

Properties not included are the same as esters

Question 25

Amine

Answer 25

- N-R - Nitrogen single bonded to a carbon - Can be primary, secondary, tertiary, or quaternary

Question 26

Amine Properties

Answer 26

Solubility- very hydrophillic Interactions- both ionic and hydrogen bond Ionization states- pKa 9-11 99% + ve at pH7, 100 % +ve at pH 1 Chemical stability- Pretty stable Biological Reactivity- can be site of phase 2 metabolism, deamination, N-demethylation by enzymes such as P450 Uses in drug structures- ionic bonder, H bond acceptor & donor: ↑H2O solubility How common- very common Prodruggability- easy conversion to amide

Question 27

Amide

Answer 27

- Similar to ester, except a dehydration of an amine and an alcohol - R'NH-C=O

Question 28

Amide Properties

Answer 28

Solubility- amphiphilic Interactions- hydrogen bond donor & acceptor Ionization states- none at biological pH Chemical stability- Stable unless water present, hydrolysis Biological Reactivity- Hydrolysis but Much less than esters (why) Uses in drug structures- To “hide” polar groups as prodrug to increase permeability across membranes. Also as H bond donor & acceptor in molecules that are not prodrugs How common- quite common Prodruggability- it IS a prodrug form of amine & acid

Question 29

Aromatic Nitrogen Heterocycles Properties

Answer 29

``` Solubility- moderate hydrophobic, much less than aliphatic amine Interactions- hydrogen bond Ionization states- generally non Chemical stability- stable Biological Reactivity- generally low Uses in drug structures- structural element also containing H bond acceptor & some are donor: can prevent metabolic toxicity as phenyl bioisostere How common- very common Prodruggability- none ```