advanced medicinal & pharmaceutical chemistry chem 5412 dept. of

Advanced Medicinal & Pharmaceutical Chemistry

Dai Lu, Ph.D. [email protected] Tel: 361-221-0745 Office: RCOP, Room 307

CHEM 5412 Dept. of Chemistry, TAMUK

mailto:[email protected]

Drug Discovery and Development

Medicinal and pharmaceutical chemistry are the sciences of how drugs can be designed and developed.

Drug Molecules

Small, chemically manufactured molecules (SMOLs ) are the classic active substances and make up over 90 percent of the drugs on the market today.

Generally, they are organic compounds with molecular weight (MW) less than 900 Daltons (Da). Most often the drug’s molecular weight (MW) is less than 500 Da.

Small molecule drugs:

Macro-molecules:

Nucleic acids, proteins, and polysaccharides (MW: 1K-150 KDa).

Drug Targets

Proteins

Receptors Enzymes Transport proteins

Nucleic Acids

Drug Targets: Proteins

R

H3N CO2

H

1. The building blocks for proteins: Amino acids

Head group (zwitterion)

Residue or side chain R

H3N CO2

H

R

H3N CO2

H

Amino acids are small molecules containing an amino group (-NH2), a carboxyl group (-COOH), a hydrogen atom, a carbon atom, and a side chain that differs among amino acids.

The identity and unique chemical properties of each amino acid are determined by the nature of the R group.

• 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

1. The building blocks for proteins: Amino acids •There are 20 common amino acids in human proteins

R

H3N CO2

H

• Each amino acid has an identical head group, but different side chain R

• 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)

Fischer diagram

CO2

R

HH3N


How to determine whether a stereocenter has R or S stereochemistry--i.e., how to name the "absolute configuration" of a chiral carbon? http://chemwiki.ucdavis.edu/Organic_Chemistry/Chirality/Absolute_Configuration,_R-S_Sequence_Rules

http://chemwiki.ucdavis.edu/Organic_Chemistry/Chirality/Absolute_Configuration,_R-S_Sequence_Rules




Structures of Proteins

Only when a protein is in its correct three dimensional structure, or conformation, it is able to function efficiently.

A key concept in understanding how proteins work is that function is derived from three dimensional structure, and the three dimensional structure is in turn specified by the amino acid sequence.

The structure of proteins can be considered at four levels of organization starting with their primary structure sequence.

Primary (sequence)

Secondary (local folding)

Tertiary (long rang folding)

Quaternary (multimeric organization)



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

HN

NH

HN

O

O

O

Protein chain Protein chain

R2

R3R1

This has an important consequence for protein tertiary structure.


The planar peptide bonds indirectly play an important role in tertiary structure. Since bond rotation is hindered in peptide bonds with the trans configuration generally favored, the number of possible confirmations that a protein can adopt is significantly limited.

This partial double bond is sufficient to stop free rotation about the C-N bond. This has an important consequence for protein tertiary structure.


• Example - Met enkephalin

Peptide backbone H2N

O

O

O

O

CO2H

SMeHO

NH

HN

NH

HN

Met

Phe

Tyr

Gly

Gly

Residues

Residues

N-terminus C-terminus

Secondary structure refers to the shape of a folding protein due exclusively to hydrogen bonding between its backbone amino (NH) and carbonyl groups (C=O).

Secondary structure does not include bonding between the R-groups

of amino acids.

The two most commonly encountered secondary structures of a polypeptide chain are α-helices and β-pleated sheets.

These structures are the first major steps in the folding of a polypeptide chain, and they establish important topological motifs that dictate subsequent tertiary structure and the ultimate function of the protein.

3. The secondary structure of proteins


Helices (α-helix, π-helix, 310 helix), Pleated sheets (α-, β-pleated sheets ) Tight turns


α-helices

An alpha-helix is a right-handed coil of amino-acid residues on a polypeptide chain, typically ranging between 4 and 40 residues. The coil is held together by H-bonds between the oxygen of C=O on top coil and the hydrogen of N-H on the bottom coil. Such a hydrogen bond is formed exactly every 5 amino acid residues because the H-bond needs to be in a linear orientation .

C

O

H

N


Β-Pleated sheets

The beta - pleated sheet is a secondary structure found in proteins in which H-bonds are formed between two parts of the protein chain that can be far apart.

Β-Pleated sheets ( anti-parallel and parallel)

anti-parallel

parallel

N to C N to C

N to C C to N


Anti-parallel β sheet formed by two H-bonds within the same amino acid residues. Parallel β sheet formed by two H-bonds with two different amino acid residues.

It is well known that helices and ß-sheets are the major stabilizing structures in proteins. Segments of the protein chain which are not helical nor ß-sheet have been generally designated as random coil or irregular regions. These nonrepetitive motif elements include tight turns, bulges, and random coil structures


Turns play an important role in globular proteins from both structural and functional points of view. A polypeptide chain cannot fold into a compact structure without the component of turns.

Also, turns usually occur on the exposed surface of proteins and hence probably represent antigenic sites or involve molecular recognition.


TIGHT TURNS


Alpha-turn - An alpha-turn involves 5 amino acid residues where the distance between the Cα (i) and the Cα (i+4) is less than 7Å and the pentapeptide chain is not in a helical conformation. Beta-turn - A beta-turn involves 4 amino acid residues and may or may not be stabilized by the intraturn hydrogen bond between the backbone CO(i) and the backbone NH(i+3). Gamma-turn - It involves 3 amino acid residues and the intraturn hydrogen bond for a gamma-turn is formed between the backbone CO(i) and the backbone NH(i+2). Delta-turn - It is the smallest tight turn which involves only 2 amino acid residues and the intraturn hydrogen bond for a delta-turn is formed between the backbone NH(i) and the backbone CO(i+1). Pi-turn - It is the largest tight turn which involves 6 amino acid residues.

TIGHT TURNS

Beta-turn


A ß-turn consists of four consecutive residues defined by positions i, i+1, i+2, i+3 which are not present in alpha-helix; the distance between Cα (i) and Cα (i+3) is less than 7Å.

4. The tertiary structure of proteins

1. Disulfide linkages

2. Hydrogen Bonding

3. Electrostatic interactions

4. Hydrophobic interactions

The interactions of the R groups give a protein its specific three-dimensional tertiary structure.

4. The tertiary structure of proteins

Bond strength: Covalent (S-S) > Ionic (salt bridge)> H-bonds> van der Walls

Importance: Covalent (S-S) < Ionic (salt bridge)< H-bonds< van der Walls

5. The quaternary structure of proteins

van der Waals interactions

Hydrophobic regions

Only proteins that are made up of multiple subunits have quaternary structures.

5. The quaternary structure of proteins

Hemoglobin

6. Protein function

As structural proteins - tubulin

6. Protein function

Enzymes - life’s catalysts Receptors - life’s communication system

6. Protein function

Transport proteins

Polar molecule

Transport protein

advanced medicinal & pharmaceutical chemistry chem 5412 dept. of

Documents