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