advanced medicinal & pharmaceutical chemistry chem 5412 dept. of
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Advanced Medicinal & Pharmaceutical Chemistry
Dai Lu, Ph.D. dlu@tamhsc.edu Tel: 361-221-0745 Office: RCOP, Room 307
CHEM 5412 Dept. of Chemistry, TAMUK
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
1. The building blocks for proteins: Amino acids
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
1. The building blocks for proteins: Amino acids
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
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)
Structures of Proteins
Structures of Proteins
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.
2. The primary structure of proteins
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.
2. The primary structure of proteins
• 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
3. The secondary structure of proteins
Helices (α-helix, π-helix, 310 helix), Pleated sheets (α-, β-pleated sheets ) Tight turns
3. The secondary structure of proteins
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
3. The secondary structure of proteins
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
3. The secondary structure of proteins
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
3. The secondary structure of proteins
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.
3. The secondary structure of proteins
TIGHT TURNS
3. The secondary structure of proteins
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
3. The secondary structure of proteins
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
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