patrick4e ch02 pdf
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An introduction to medicinal chemistry 4ed Ch02TRANSCRIPT
Patrick: An IntroductionPatrick: An Introductiontoto MedicinalMedicinal Chemistry 4eChemistry 4e
Chapter 02Chapter 02
DRUG TARGETS:DRUG TARGETS:PROTEINSPROTEINS
1. The building blocks for proteins1. The building blocks for proteins
• Proteins are macromolecules made up of amino acid building blocks
• There are 20 common amino acids in human proteins
R
H3N CO2H Head groupHead group
(zwitterion)(zwitterion)
Residue Residue or side chainor side chainR
H3N CO2H
R
H3N CO2H
1. The building blocks for proteins1. 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 -amino acids are -enantiomers
R
H3N CO2H
• The L-amino acids are S-enantiomers (except cysteine; R = CH2SH)
Fischer diagramFischer diagram
CO2
R
HH3N
1. The building blocks for proteins1. The building blocks for proteins
• Codes for amino acids
AlanineAlanine AlaAla AAArginineArginine ArgArg RRAsparagineAsparagine AsnAsn NNAspartic acidAspartic acid AspAsp DDCysteineCysteine CysCys CC
HistidineHistidine HisHis HHIsoleucineIsoleucine IleIle IILeucineLeucine LeuLeu LLLysineLysine LysLys KKMethionineMethionine MetMet MM
Glutamic acidGlutamic acid GluGlu EEGlutamineGlutamine GlnGln QQGlycineGlycine GlyGly GGProlineProline ProPro PPSerineSerine SerSer SSTyrosineTyrosine TyrTyr YY
PhenylalaninePhenylalanine PhePhe FFThreonineThreonine ThrThr TTTryptophanTryptophan TrpTrp WWValineValine ValVal VV
1. The building blocks for proteins1. The building blocks for proteins
• Examples of amino acids
CH3
H3N CO2H
H3N CO2H
H3N CO2H
HOH3C CH3
H3N CO2H
CO2
H3N CO2H
H3N CO2H
NH3
CH3
H3N CO2H
H3N CO2H
H3N CO2H
HOH3C CH3
H3N CO2H
CO2
H3N CO2H
H3N CO2H
NH3
AlanineAlanine ValineValine SerineSerine
AspartateAspartate
LysineLysinePhenylalaninePhenylalanine
2. The primary structure of proteins2. 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 bondsPeptide bonds
HN
NH
HN
O
O
O
Protein chain Protein chain
R2
R3R1
Peptide bondsPeptide bonds
HN
NH
HN
O
O
O
Protein chain Protein chain
R2
R3R1
2. The primary structure of proteins2. The primary structure of proteins
• Example - Met enkephalin
Peptide backbonePeptide backboneH2N
O
O
O
O
CO2H
SMeHO
NH
HN
NH
HN
PhePhe
GlyGly
ResiduesResidues
Peptide backbonePeptide backboneH2N
O
O
O
O
CO2H
SMeHO
NH
HN
NH
HN
MetMetTyrTyr
GlyGlyResiduesResidues
3. The secondary structure of proteins3. The secondary structure of proteins
C
O
C
NH
NH
C
O
NH
C
O
C
NH
NH
C
O
NH
The a-helix
R
R
RR
C
O
C
O
NH
NH
C
O
C
ONH
NH
C
O
C
O
NH
NH
C
O
C
ONH
NH
a-Helical backbone Position of residuesHydrogen bondingbetween peptide bonds
R
R R
R
R
3. The secondary structure of proteins3. The secondary structure of proteins
Residuesabove ß-pleated sheet
• The b-pleated sheet
NH
N
O
N
H
O H
O
N
H
O
NH
ON
H
OR R R
R R R
Residuesbelow ß-pleated sheet
NO
H ONH O
NH O
NH O
N
H ONH
RR R R
4. The tertiary structure of proteins4. The tertiary structure of proteins
Repulsive Interactions
H2N
MeMe Me
OH
OH NH3
O NH2
NH3 CO2
H2OH2O H2O
Van der Waals interactionsHydrogen bonding interactionsIonic bonding interactions
H2O
H2O
H2O
Me
Me
Me
CO2NH3
NH3NH2
O
HO
H2N
4. The tertiary structure of proteins4. The tertiary structure of proteins
Covalent bonds - disulfide links
Covalentbond
SH HS S SCys Cys
Cys Cys
4. The tertiary structure of proteins4. The tertiary structure of proteins
Ionic or electrostatic bonds (salt bridges)
Ionic bond(salt bridge)
CO2(CH2)4H3N
AspLys
4. The tertiary structure of proteins4. The tertiary structure of proteins
Hydrogen bonds
Ser Ser
H-bond H-bond
d+ d-
d+
d-O
H
OHSer
OAsp
Od+ d-
OH
4. The tertiary structure of proteins4. The tertiary structure of proteins
Van derWaals interactions
LeuVal
H3C CH3 H3C CH3
van der Waalsinteractions
4. The tertiary structure of proteins4. The tertiary structure of proteins
HH OH
O
H
H
HO H
OH
H
H-bond
H-bond
PeptidechainPeptide
chain
O H
CH2
CH2
CH2CO2
Me Me
Phe
Ser
Asp
Val
Hydrophobiccentre
H
O H
OH
H
H O
H
O
H
H
H O
H
H H
Protein
H2NOH
CO2
Me
H3N
HO
MeMe
Folding
5. The quaternary structure of proteins5. The quaternary structure of proteins
van der Waalsinteractions
Hydrophobic regions
6. Protein function6. Protein function
PolymerizationPolymerization
Structural proteins Structural proteins -- tubulintubulin
TubulinTubulin
DepolymerizationDepolymerization
MicrotubuleMicrotubule
Polar molecule
6. Protein function6. Protein function
Transport proteins
Transportprotein
6. Protein function6. Protein function
Enzymes - life’s catalystsReceptors - life’s communication system