Patrick: An Introduction

to Medicinal Chemistry 4e
Chapter 02
DRUG TARGETS:
PROTEINS

1. The building blocks for proteins

Proteins are macromolecules made up of amino acid building
blocks
There are 20 common amino acids in human proteins

H
H3N

CO2
R

Head group
(zwitterion)
Residue
or side chain

1. The building blocks for proteins

Each amino acid has an identical head group
Amino acids are chiral molecules
(except glycine, R=H)
Naturally occurring amino acids are the L-form
The L-amino acids are S-enantiomers
(except cysteine; R = CH2SH)
H
H3N

CO2
R

CO2
H3N

H
R

Fischer diagram

1. The building blocks for proteins

Codes for amino acids
Alanine
Arginine
Asparagine
Aspartic acid
Cysteine
Glutamic acid
Glutamine
Glycine
Proline
Serine
Tyrosine

Ala
Arg
Asn
Asp
Cys
Glu
Gln
Gly
Pro
Ser
Tyr

A
R
N
D
C
E
Q
G
P
S
Y

Histidine
Isoleucine
Leucine
Lysine
Methionine
Phenylalanine
Threonine
Tryptophan
Valine

His
Ile
Leu
Lys
Met
Phe
Thr
Trp
Val

H
I
L
K
M
F
T
W
V

1. The building blocks for proteins

Examples of amino acids

H3N

H
CO2
CH3

Alanine

H3N

CO2

H3N

H3C

CH3

HO

Valine

H
CO2

Serine

H3N

CO2

H3N

CO2

H
H3N

CO2

CO2

Aspartate

NH3

Lysine

Phenylalanine

2. The primary structure of proteins

The primary structure is the order in which the amino acids are
linked together
The amino acids are linked through their head groups by
peptide bonds to form a polypeptide chain or backbone
Peptide bonds
R2

H
N

H
N

Protein chain
R1

N
H

Protein chain
O

R3

2. The primary structure of proteins

Example - Met enkephalin

Phe
Residues
O
H 2N

Gly

H
N

N
H
O

H
N

Gly

N
H
O

Tyr

Peptide backbone
Residues

SMe
HO

CO2H

Met

3. The secondary structure of proteins

The a-helix

H
NC

O
H
N C

H
NC

O
H
NC

a-Helical backbone

H
NC

H
NC

Hydrogen bonding
between peptide bonds

H
N C

H
NC

R O

O
H
NC

H
NC

RO

Position of residues

3. The secondary structure of proteins

The b-pleated sheet
Residues
above
-pleated sheet
R
O

N
H

N
N

N
N
H

N
R

N
H

H
N

O
H
N

R
Residues
below
-pleated sheet

4. The tertiary structure of proteins

Me

Me

O
OH

Me

H2N

OH

Repulsive Interactions

NH2

NH3

NH3

CO2

Van der Waals interactions

Hydrogen bonding interactions
Ionic bonding interactions

H2O

H2O

H2O
NH2

NH3

O
H2O

NH3 CO2

HO
H2O
Me
H2N

Me
Me

4. The tertiary structure of proteins

Covalent bonds - disulfide links

Covalent
bond

Cys

SH

HS

Cys

S
Cys

S
Cys

4. The tertiary structure of proteins

Ionic or electrostatic bonds (salt bridges)

Ionic bond
(salt bridge)

CO2
Asp

H3N

(CH2)4
Lys

4. The tertiary structure of proteins

Hydrogen bonds

H-bond

H-bond
Ser
Ser

dO
H
d+

H O
d+ d-

Ser
O
Asp
O

H O
d+ d-

4. The tertiary structure of proteins

Van derWaals interactions

Leu
H3 C

Val
CH3

H3 C

van der Waals

interactions

CH3

4. The tertiary structure of proteins

H-bond

H
O

Ser O H

O
H
Me

CH2

Me

Val
Peptide
chain

Peptide
chain
CH2

CH2

Asp

Phe

H
CO2

H O

H-bond
H

Folding

H2N
H
H

OH

Me

O
HO
Hydrophobic
centre

H
H

Me

H3N
Protein

Me

CO2
H

O
H

5. The quaternary structure of proteins

van der Waals

interactions

Hydrophobic
regions

6. Protein function
Structural proteins - tubulin

Polymerization
Depolymerization

Tubulin

Microtubule

6. Protein function
Transport proteins

Polar molecule

Transport
protein

6. Protein function
Enzymes - lifes catalysts
Receptors - lifes communication system