patrick-chapter2

1. © Oxford University Press, 2013
DRUG TARGETS
PROTEINS
Patrick: An Introduction
to Medicinal Chemistry 6e
Chapter 2

2. © Oxford University Press, 2013
R
H3N CO2
H
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
Head group
(zwitterion)
Side chain
R
H3N CO2
H
R
H3N CO2
H

3. © Oxford University Press, 2013
R
H3N CO2
H
1. The building blocks for proteins
• Each amino acid has an identical head group
• Amino acids are chiral molecules
(except glycine, R=H)
• Only L-amino acids are present in human biochemistry
• The L-amino acids are S-enantiomers
(except cysteine; R = CH2SH)
Fischer diagram
CO2
R
H
H3N

4. © Oxford University Press, 2013
1. The building blocks for proteins
• Codes for amino acids
Alanine Ala A
Arginine Arg R
Asparagine Asn N
Aspartic acid Asp D
Cysteine Cys C
Glutamic acid Glu E
Glutamine Gln Q
Glycine Gly G
Proline Pro P
Serine Ser S
Tyrosine Tyr Y
Histidine His H
Isoleucine Ile I
Leucine Leu L
Lysine Lys K
Methionine Met M
Phenylalanine Phe F
Threonine Thr T
Tryptophan Trp W
Valine Val V

5. © Oxford University Press, 2013
1. The building blocks for proteins
• Examples of amino acids
C
H
3
H
3
N C
O
2
H
H
3N C
O
2
H
H
3N C
O
2
H
H
O
H
3C C
H
3
H
3N C
O
2
H
C
O
2
H3N CO2
H
H3N CO2
H
NH3
Alanine Valine Serine
Aspartate
Lysine
Phenylalanine

6. © Oxford University Press, 2013
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
H
N
Protein chain N
H
O
H
N
O
Protein chain
O
R3
R1
R2

7. © Oxford University Press, 2013
2. The primary structure of proteins
• Example - Met enkephalin
Peptide backbone
Met
Phe
Tyr
Gly
Gly
Side chains
Side chains

8. © Oxford University Press, 2013
3. The secondary structure of proteins
C
O
C
O
C
O
N
H
N
H
N
H
C
O
C
O
C
O
N
H
N
H
C
O
C
O
C
O
N
H
N
H
N
H
C
O
C
O
C
O
N
H
N
H
The a-helix
a-Helical backbone Position of side chains
Hydrogen bonding
between peptide bonds
R
R
R
R
R R
R
R
R
Regions of regular structure within a protein

9. © Oxford University Press, 2013
3. The secondary structure of proteins
Side chains
above b-pleated
sheet
Side chains
below
ß-pleated sheet
• The b-pleated sheet
N
O
H O
N
H O
N
H O
N
H O
N
H O
N
H
N
H
N
O
N
H
O H
O
N
H
O
N
H
O
N
H
O
R
R
R
R R
R
R
R R R
Regions of regular structure within a protein

10. © Oxford University Press, 2013
4. The tertiary structure of proteins
Repulsive Interactions
H2O
H2O
H2O
H2O H2O
Van der Waals interactions
Hydrogen bonding interactions
Ionic bonding interactions
Me
Me
Me
CO2
NH3
NH3
NH2
O
HO
H2N
+
+
H2N
Me
Me Me
OH
OH NH3
O NH2
NH3 CO2
+ +
•Overall shape of the protein
•Maximises favourable interactions and minimises respulsive
interactions

11. © Oxford University Press, 2013
4. The tertiary structure of proteins
S H H S S S
Cys Cys
Covalent bonds - disulphide links
Cys Cys
Covalent
bond

12. © Oxford University Press, 2013
4. The tertiary structure of proteins
Ionic or electrostatic bonds (salt bridges)
CO2
(CH2)4
H3N
Asp
Lys
Ionic bond
(salt bridge)

13. © Oxford University Press, 2013
4. The tertiary structure of proteins
Hydrogen bonds
d+ d-
d+
d-
O
H
O
H
Ser
Ser
O
Asp
O
d+ d-
O
H
Ser
H-bond H-bond

14. © Oxford University Press, 2013
4. The tertiary structure of proteins
Van derWaals interactions
Leu
Val
H3C CH3 H3C CH3
van der Waals
interactions

15. © Oxford University Press, 2013
4. The tertiary structure of proteins
Hydrophobic
centre
H
O H
O
H
H
H O
H
O
H
H
H O
H
H
O
H
O
H
H
H
O
H
O
H
H
Protein
H2N
OH
CO2
Me
H3N
HO
Me
Me
Folding
H-bond
H-bond
Peptide
chain
Peptide
chain
O
H
CH2
CH2
CH2CO2
Me Me
Phe
Ser
Asp
Val

16. © Oxford University Press, 2013
5. The quaternary structure of proteins
van der Waals
interactions
Hydrophobic
regions
Arrangement of protein subunits with respect to each other

17. © Oxford University Press, 2013
6. Protein function
Tubulin
Polymerization
Depolymerization
Microtubule
Structural proteins - tubulin

18. © Oxford University Press, 2013
Polar molecule
6. Protein function
Transport proteins
Transport
protein
•Transport polar molecules across the hydrophobic cell membrane
•Polar molecules transported include amino acids and neurotransmitters

19. © Oxford University Press, 2013
6. Protein function
Enzymes
•Act as catalysts for reactions within the cell
•Present on the inner surface of the cell membrane or within the cell
•Bind the substrates for a reaction and release products
Receptors
•Present in the cell membrane or within the cell
•Act as the cell’s ‘post boxes’
•Receive chemical messages from neurotransmitters and hormones
•Initiate or inhibit chemical signalling processes within the cell