Introduction to Medicinal Chemistry - Amino Acids 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. * Each amino acid has a central carbon, called th...

## 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. * Each amino acid has a central carbon, called the **alpha-carbon**, attached to four groups: * **Hydrogen atom (H)** * **Amino group (NH2)** * **Carboxyl group (COOH)** * **R group** (a side chain that distinguishes each amino acid) * **Zwitterion:** An amino acid in solution exists as a **zwitterion**, which means it has both a positive and a negative charge. This is because at neutral pH, the amino group is protonated (NH3+) and the carboxyl group is deprotonated (COO-), resulting in a net charge of zero. ### ** Amino Acids** * **Nonzwitterions:** The non-ionized form of amino acids, where the amino group is not protonated and the carboxyl group is not deprotonated. * **Zwitterions:** The ionized form of amino acids where the amino group is protonated and the carboxyl group is deprotonated. ### **Chirality** * Amino acids are chiral molecules (with the exception of glycine, where R = H). * **Chiral center:** The alpha-carbon is a chiral center since it is bonded to four different groups. * **Enantiomers:** The two mirror images of an amino acid are called enantiomers (L form or D form). The L-isomer is the form found in nature and in human biochemistry. ### **R, S system** * **R:** The **R configuration** of amino acids is assigned with priority based on the Cahn-Ingold-Prelog rules. The priority of the groups is given based on their atomic numbers (O > N > C > H). The **R-form means that the lowest priority group (H) is pointing away from the viewer. * **S:** The **S configuration** follows the same rules but the lowest priority group points towards the viewer. ### **Nomenclature** * **L-amino acids**: The L-amino acids are also known as **R-enantiomers**. * **D-amino acids:** The D-amino acids are also known as **S-enantiomers**. * **Fischer Diagrams** are traditionally used to represent amino acids. ### **Codes** * **3-letter code:** Ala, Arg, Asn, Asp, Cys, Glu, Gln, Gly, His, lle, Leu, Lys, Met, Phe, Pro, Ser, Thr, Trp, Tyr, Val * **One-letter code:** A, R, N, D, C, E, Q, G, H, I, L, K, M, F, P, S, T, W, Y, V ### **Guide To Common Amino Acids** The table below summarizes 20 common amino acids, their chemical structure, and their properties (aliphatic, aromatic, acidic, basic, hydroxyl, sulfur-containing, amidic, non-essential and essential). | Amino Acid | Chemical Structure | Properties | |---|---|---| | **Alanine** | Aliphatic | Non-essential | | **Glycine** | Aliphatic | Non-essential | | **Isoleucine** | Aliphatic | Essential | | **Leucine** | Aliphatic | Essential | | **Proline** | Aliphatic | Non-essential | | **Valine** | Aliphatic | Essential | | **Phenylalanine** | Aromatic | Essential | | **Tryptophan** | Aromatic | Essential | | **Tyrosine** | Aromatic | Non-essential | | **Aspartic Acid** | Acidic | Non-essential | | **Glutamic Acid** | Acidic | Non-essential | | **Arginine** | Basic | Non-essential | | **Histidine** | Basic | Essential | | **Lysine** | Basic | Essential | | **Serine** | Hydroxylic | Non-essential | | **Threonine** | Hydroxylic | Essential | | **Cysteine** | Sulfur-containing | Non-essential | | **Methionine** | Sulfur-containing | Essential | | **Asparagine** | Amidic | Non-essential | | **Glutamine** | Amidic | Non-essential | ### **Willie Taylor's Scheme** Willie Taylor's scheme provides a grouping of 20 common amino acids based on their chemical properties (hydrophobic, polar, charged + and charged -). | Properties | Amino Acids | |---|---| | Hydrophobic| Glycine, Alanine, Valine, Proline, Leucine, Isoleucine, Phenylalanine, Tryptophan, Methionine | | Polar | Serine, Threonine, Cysteine, Tyrosine | | Charged (+) | Lysine, Arginine, Histidine | | Charged (-) | Aspartic Acid, Glutamic Acid, Glutamine, Asparagine | ### **Glucogenic and Ketogenic Amino Acids** Amino acids can be classified as **glucogenic** (can be converted to glucose), **ketogenic** (can be converted to ketone bodies), or both. * **Glucogenic:** Alanine, Glycine, Threonine, Cysteine, Serine, Tryptophan * **Ketogenic:** Tryptophan, Tyrosine, Isoleucine, Lysine, Leucine * **Both:** Aspartate, Asparagine ### **2. The Primary Structure of Protein** * The primary structure of a protein refers to the linear sequence of amino acids in a polypeptide chain. * **Peptide bond:** Amino acids are linked together by peptide bonds, which are formed between the carboxyl group of one amino acid and the amino group of another amino acid. * **N-terminus:** The N-terminal end of a polypeptide chain has a free amino group. * **C-terminus:** The C-terminal end of a polypeptide chain has a free carboxyl group. **Diagram:** The primary structure of a protein is represented as a chain of amino acids. The peptide bond between amino acids (1) and (2) is formed, releasing a water molecule. ### **3. The Secondary Structure of Protein** * The secondary structure of a protein describes the local folding patterns of the polypeptide chain, which are stabilized by hydrogen bonds. * The two most common secondary structures are: * **Alpha helix:** A helical structure where the polypeptide chain coils around a central axis. * **Beta sheet:** A sheet-like structure formed by hydrogen bonds between adjacent polypeptide chains. Beta sheets can be parallel (strands running in the same direction) or antiparallel (strands running in opposite directions). * **Phi and Psi Torsion Angles:** These angles describe the rotation around the bonds of the alpha-carbon, which influences the formation of secondary structures. * **Ramchandran Plot:** This plot shows the allowed and disallowed combinations of phi and psi angles in protein structures. **Diagrams:** * The secondary structure of a protein is represented by a helical structure (alpha helix) and a sheet structure (beta sheet). * The formation of alpha helix and beta sheet is explained with the help of phi and psi angles. * The 3D Ramachandran plot represents the allowed and disallowed combinations of phi and psi angles. ### **4. The Tertiary Structure of Protein** * The tertiary structure of a protein describes the three-dimensional, or global, shape of a polypeptide chain. * The tertiary structure is determined by interactions between R groups, including: * **Hydrogen bonds** * **Hydrophobic interactions** * **Ionic bonds (salt bridges)** * **Disulfide bonds** (covalent bonds between cysteine residues) * **Overall Shape of the protein:** The tertiary structure maximizes favorable interactions and minimizes repulsive interactions, leading to a stable conformation. **Diagrams** * The tertiary structure of a protein is represented by a complex, 3D structure. * The different interactions that stabilize tertiary structure are explained with the help of diagrams, including hydrogen bonds, hydrophobic interactions, ionic interactions, and disulfide bonds. ### **5. The Quaternary Structure of Proteins** * The quaternary structure of proteins refers to the arrangement of multiple polypeptide chains (subunits) in a protein complex. * This structure is stabilized by the same types of interactions that stabilize the tertiary structures: hydrogen bonds, hydrophobic interactions, ionic bonds, and disulfide bonds. **Diagram:** The quaternary structure of a protein is represented by the arrangement of multiple polypeptide chains. ### **6. Protein Function** * **Structural Proteins:** Provide shape and support to cells and tissues. * **Tubulin**: An example of a structural protein that forms microtubules, which are cellular structures that help with cell division, transport, and movement. **Diagram:** The microtubules are formed through polymerization of tubulin. * **Transport Proteins:** Facilitates the movement of molecules across cell membranes. * **Transport polar molecules:** Transport proteins help polar molecules across the hydrophobic cell membrane, including amino acids and neurotransmitters. **Diagram:** The transport of polar molecules across the cell membrane is facilitated by transport proteins and carrier proteins. **Article: ** Binding of The Zn2+ Ion To Ferric Uptake Regulation Protein From E. Coli And The Competition With Fe2+ Binding: A Molecular Modeling Study Of The Effect On DNA Binding And Conformation Changes Of Fur **This article** discusses the role of the Zn2+ ion in the ferric uptake Regulation protein (Fur) from E. coli. It investigates how the binding of Zn2+ affects the interaction of Fur with DNA and the overall conformation of the protein. Using molecular modeling, the study explores the competition between Zn2+ and Fe2+ binding to Fur and the impact of these interactions on the protein's function. The article focuses on the following key points: * **Fur Structure:** The Fur protein from E. coli plays a role in regulating iron uptake. It interacts with DNA and functions as a transcriptional repressor. * **Zn2+ Binding and Competition:** The authors found that Zn2+ binds to Fur and competes with Fe2+ for binding. This competition can affect the protein's conformation and influence its interaction with DNA. * **Conformational Changes:** The study investigated the conformational changes in Fur triggered by the binding of Zn2+ and Fe2+. This conformational flexibility is crucial for the protein's function, including its ability to bind to DNA sequences involved in iron metabolism. * **Molecular Modeling:** The study employed molecular modeling techniques to simulate and analyze the interactions between Fur, Zn2+, Fe2+, and DNA. These techniques provide insights into the structural dynamics and functional mechanisms of the protein. This research contributes to our understanding of how trace elements like Zn2+ can impact protein function and alter cellular processes. The insights gained from this study could be relevant for developing new therapeutics targeting metal-dependent proteins or for understanding the role of trace elements in cellular regulation.