Introduction to Medicinal Chemistry - Drug Targets: Proteins - PDF

# An Introduction to Medicinal Chemistry ## Chapter 3: Drug Targets: Proteins ### 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. ### 2. Amino Acids - **Non-ionized form of amino a...

# An Introduction to Medicinal Chemistry ## Chapter 3: Drug Targets: Proteins ### 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. ### 2. Amino Acids - **Non-ionized form of amino acids:** - The amino group has a hydrogen atom attached to it (*NH2*), and the carboxyl group has a hydroxyl group attached to it (*COOH*). - **Ionized form of amino acids (zwitterion):** - The amino group picks up a proton (*NH3+*), and the carboxylic group loses a proton (*COO-*). ### 3. Zwitterions - Formerly called a **dipolar ion**, a zwitterion is a molecule with two or more functional groups, of which at least one has a positive and one has a negative electrical charge, and the net charge of the entire molecule is zero. - **Cation** * NH3+ * R - C - COOH * H - **Zwitterion**: * NH3+ * R - C - COO- * H - **Anion**: * NH2 * R - C - COO- * H ### 4. Amino acids are **chiral** molecules (except **glycine**, R=H) - **Chiral center** - * H - * H - N - * C - C - OH - * R * Amino Group * Carboxyl Group * Side Chain - **Mirror image** → **nonsuperimposable mirror images** - **Enantiomers** → **isomers** L (R), D (S) ### 5. General Amino Acid features - **Chirality and the R, S system** - H < C < N < O #### R-isomer (L) - The arrangement of the groups is **clockwise**: - O= - - O C - +H3N C H / R #### S-isomer (D) - The arrangement of the groups is **counterclockwise**: - O= - O C - H C NH3+ \ R #### Fisher Diagram (looking at the chiral carbon) - **R-isomer (L):** - COOH - | - H - C - H - | - NH2 - | - R - L-amino acid - **S-isomer (D):** - COOH - | - H - C - NH2 - | - R - | - H - D-amino acid ### 6. Amino acids: a summary - 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 **R-enantiomers**. (except **cysteine**: R = CH2SH) ### 7. Codes for amino acids | NAME | 3 LETTER CODE | ONE LETTER CODE | |:---------------------:|:----------------:|:----------------:| | 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 | | Histidine | His | H | | Isoleucine | Ile | I | | Leucine | Leu | L | | Lysine | Lys | K | | Methionine | Met | M | | Phenylalanine | Phe | F | | Proline | Pro | P | | Serine | Ser | S | | Threonine | Thr | T | | Tryptophan | Trp | W | | Tyrosine | Tyr | Y | | Valine | Val | V | ### 8. A Guide to the twenty common amino acids - **Chart Key** - **Aliphatic** - Alanine - Glycine - Isoleucine - Leucine - Proline - Valine - **Aromatic** - Phenylalanine - Tryptophan - Tyrosine - **Acidic** - Aspartic Acid - Glutamic Acid - **Basic** - Arginine - Histidine - Lysine - **Hydrolyic** - Serine - Threonine - **Sulphur containing** - Cysteine - Methionine - **Amidic** - Asparagine - Glutamine - **Non-essential** - All amino acids except for: - **Essential** - Histidine - Isoleucine - Leucine - Lysine - Methionine - Phenylalanine - Threonine - Tryptophan - Valine ### 9. Willie Taylor's scheme - This scheme classifies amino acids using polarity and hydrophobicity. - The scheme is used for studying the structure and function of proteins. - **Hydrophobic** - Glycine - Alanine - Proline - Leucine - Valine - Tryptophan - Isoleucine - Methionine - **Polar** - Serine - Cysteine - Threonine - Tyrosine - **Charged (-)** - Glutamine - Asparagine - Glutamic Acid - Aspartic Acid - **Charged (+)** - Histidine - Lysine - Arginine ### 10. Metabolic fates of amino acids - **Ketogenic** - Tryptophan - Tyrosine - Phenylalanine - Threonine - Isoleucine - Leucine - **Glucogenic** - Alanine - Glycine - Serine - Cysteine - Aspartate - Asparagine - Glutamate - Proline - Arginine - Histidine - Glutamine - Methionine - Isoleucine - Valine - **Both Ketogenic and Glucogenic** - Tryptophan - Tyrosine - Phenylalanine - Threonine - Isoleucine ### 11. The primary structure of protein - It is the linear sequence of amino acids in a polypeptide chain. - The amino acids are linked together by **peptide bonds**. - The primary structure is determined by the genetic code. ### 12. The secondary structure of protein - Folding of the polypeptide chain to form a **helix** or **sheet**. - Held together by **hydrogen bonds** between the peptide bonds. - **Alpha helix:** A right-handed helix stabilized by hydrogen bonds between the **carbonyl oxygen** of one amino acid and the **amino hydrogen** of the fourth amino acid down the chain. - **Beta sheet:** A sheet like structure stabilized by hydrogen bonds between **backbone** atoms of adjacent polypeptide chains. - **Ramachadron plot** - A map showing the possible conformations of a protein based on different angles. - The **phi** angle is the angle between the **Cα** and the **carbonyl carbon**. - The **psi** angle is the angle between the **Cα** and the **nitrogen atom**. ### 13. The tertiary structure of protein - The **three-dimensional** shape of a protein. - Determined by the interactions between **side chains**. - The tertiary structure helps the protein to function properly. - The tertiary structure can be stabilized by: - **Van der Waals interactions** - **Hydrogen bonds** - **Ionic bonds (salt bridges)** - **Covalent bonds (disulfide links)** ### 14. The quaternary structure of proteins - The arrangement of two or more polypeptide chains within a protein. - Held together by the same types of interactions that contribute to the tertiary structure. ### 15. Protein function - **Tubulin:** - A structural protein that forms **microtubules**. - Microtubules are important for cell division, transport, and maintaining cell shape. - Tubulin is a heterodimer composed of **alpha-tubulin** and **beta-tubulin** subunits. - **Transport proteins**: - Proteins that move molecules across the hydrophobic cell membrane. - **Carrier proteins** bind to molecules and transport them across the membrane. - **Channel proteins** allow molecules to pass. ### 16. Iron(II) triggered conformational changes in Escherichia coli fur upon DNA binding - This is an example of how proteins can change their shape in response to environmental changes. - This study used molecular modeling to investigate the conformational changes in the **ferric uptake regulation protein (fur)** when it binds to DNA. ### 17. Salih al-Jabour: Dr.rar.nat - His expertise is in scientific research and teaching. - His work is cited many times in the study mentioned above, about iron(II) triggered conformational changes in Escherichia coli fur upon DNA binding.