CHEM 1051 Mid-Term 1 Exam Notes PDF

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CHEM 1051 Mid-Term 1 Exam Drugs - Drug = A compound that interacts with a biological molecule, triggering a physiological effect. - Selective toxicity = Drugs that are toxic to ‘problem cells’ but not normal cells; considered effective. - Therapeutic index = Measure of a drug’s beneficial use at a low dose vs. its harmful effects at a high dose. (The > ratio = Safer drugs) - Drugs enter a complex system of chemical reactions with which they interact. - Different drugs act on molecular targets at different locations in the cell. - Drugs mainly target proteins and nucleic acids (DNA/RNA macromolecules = molecular weights in the 1000s of amu.) & also lipids + carbohydrates. - Drugs interact with a macromolecular target via a process = binding. - Specific area of the macromolecule where this takes place = binding site. - Takes the form of a hollow/ canyon - Involves intermolecular bonds. -

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Equilibrium takes place btw the drug being bound and unbound to its target. Functional groups present in the drug are important in forming intermolecular bonds with the target binding site = binding groups. Functional groups present in the target = binding regions.

Intermolecular Forces - Ionic Bonds - Strongest of these bonds. - Takes place btw groups having opposite charges. - Stronger in hydrophobic environments. - Likely to be the most important initial interaction as the drug enters the binding site.

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- Hydrogen Bonding - Takes place btw an electron-rich heteroatom and an electron-deficient hydrogen ➔ Key functional groups: HBA: Carboxylates, phosphates, ethers, alcohols, amides, amines, ketones. HBD: Ammonium ions, amines, alcohols.

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Van der Waals - Very weak interactions, there can be many such interactions in a drug and its target, so the overall contribution can be significant. - Take place btw 2 hydrophobic regions. - Strength influenced by how close the molecules are; the drug needs to be close to the binding site for it to be effective.

Molecules in 3D - sp3 hybridised carbons (4 single bonds) are tetrahedral and have 3D shape. - There are several ways to represent 3D structures; wedged and dashed bonds. Shapes of Molecules - Many of the reactions and properties of molecules are related to their shape. - Shape is dependent on bond angles and bond lengths. The concept of hybridization of atoms in a molecule to explain shape. Bonding sp3 Hybridisation - 1 s and 3 p orbitals can hybridize to form 4 equivalent sp3 orbitals. - sp3 hybrid orbitals have the large lobe of each orbital -

pointing toward the vertex of a tetrahedron. The carbon atom in CH4 has sp3 hybridization so in CH4, 4 equivalent bonds are formed by the overlap of 4 sp3 orbitals with the 1s orbitals of each of the 4 H atoms.

How to Determine Hybridisation? 1) Look at the atom. 2) Count the number of atoms connected to it (atoms – not bonds!) 3) Count the number of lone pairs attached to it. 4) Add these two numbers together. - If it’s 4, your atom is sp3. - If it’s 3, your atom is sp2. - If it’s 2, your atom is sp. - If it’s 1, it’s hydrogen. Isomerism - 2 compounds that have the same formula but different atom connections/bonds. - This results in both different chemical and physical properties. - Thus, molecular formulae are usually inadequate to represent organic compounds. - Structural formulae are needed to remove ambiguity. Structural Isomers - Aka. constitutional isomers. - Atoms connected in a different order. - Usually different physical & chemical properties. - Sometimes this effect is modest. -

Structural isomers can have different functional groups.

Stereoisomers - Same molecular formula/order of attachment of atoms but different 3D orientations of their atoms in space.

Enantiomers - A stereoisomer that is non-superimposable with its mirror image. - An object which is non-superimposable with its mirror image = Chiral. - Chirality= handedness - Have identical physical and chemical properties except for: a) the direction a solution of each of the enantiomers rotates the plane of plane polarised light (optical rotation). b) the interaction of each of the enantiomers with another chiral molecule. - A mixture of both enantiomers is known as a racemate/racemic mixture. - Racemates do not rotate plane polarized light.

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Can interconvert btw. the pair. - Accessible pathway/reaction mechanism required; doesn’t occur spontaneously. 2 Ways of Drawing Enantiomers: - Mirror image - Keep the shape of bonds the same but swap the wedges and dashes.

Chirality - Achiral objects (objects that lack chirality) possess a plane of symmetry. - Plane of symmetry: An imaginary plane passing through an object dividing it such that one half is the mirror image of the other half. - Molecules that contain a stereocentre are non-superimposable with their mirror image (i.e. they have different stereo-structures). - A stereocentre has no plane of symmetry and it must have 4 different substituents attached to it. - Criteria for chirality: 1) Does it have a stereocentre? 2) Does it have a plane of symmetry? 3) Does its mirror image non-superimposed overlapped such that both objects are visible)? If it fails any one of the above its achiral; pass all = chiral. Optical Isomers - 2 compounds which contain the same number and kinds of atoms, and bonds and different spatial arrangements of the atoms, but which have non-superimposable mirror images. - Molecules or ions that exist as optical isomers are called chiral. - Not all coordination compounds have optical isomers. - Pure samples of enantiomers have identical physical properties (e.g., boiling point, density, freezing point). Chiral molecules and ions have different chemical properties only when they are in chiral environments. - Optical isomers get their name because the plane of plane-polarized light that is passed through a sample of a pure enantiomer is rotated. The plane is rotated in the opposite direction but with the same magnitude when plane-polarized light is passed through a pure sample containing the other enantiomer of a pair.

Optical Rotation - When plane polarized light is passed through a solution of a molecule containing a stereocentre, the plane of polarized light is rotated (hence optical rotation). - This rotation is measured using a polarimeter. - The angle (α) and direction (+ or -) of rotation are both measured - + = Clockwise - - = Anti-clockwise

Chiral Interactions - A single enantiomer will interact with another chiral molecule in a different manner to its mirror image. - Enantiomers can sometimes have different biological effects: Some are trivial (differing tastes or odours) while others are more serious (of increasing importance in the pharmaceutical industry). - Sometimes there is no perceptible difference.

Nucleic Acids - Stores genetic information. - Deoxyribonucleic acid (DNA) and ribonucleic acid (RNA): Repository of an organism’s entire hereditary information, regulates the growth and division of cells. - Double helix: secondary structure of DNA wherein DNA strands are twisted into a helical form around a common axis. - Watson and Crick: DNA consists of two antiparallel strands of DNA sugar phosphate backbone on the outside and bases on the inside. - Stacking interactions: Weak attractive forces in DNA generated by favorable van der Waals interactions btw. adjacent pairs of bases. - Major & minor grooves: Spaces either above or below the planar faces of bases that offer binding opportunities for proteins and small molecules. - Polymers= Building blocks are the nucleotides. Nucleotides - Nucleotides consist of three parts: - Heterocyclic base

- Sugar - Phosphate ester Heterocycles - Replacement of a carbon atom in benzene by nitrogen gives the heterocycle pyridine.

Base Pairing

Why T vs. U IN DNA? - Thymine synthesis: Costly - requires the expenditure of ATP (1 NADPH = 3 ATP). - Cytosine can be degraded to uracil; would lead to potentially lethal mutations

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RNA -

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U in DNA is recognised as a mistake and repaired (replaced with C) before DNA synthesis continues.

RNA is more readily cleaved than DNA (i.e., is less stable as a polymer) due to the presence of an internal nucleophile (2’-OH)

DNA carries the genetic information of the cell and must remain intact during the lifespan of the cell RNA is synthesised when needed - need to get rid of it to turn off protein synthesis

DNA, RNA & Protein Synthesis

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DNA must have ATCG pairs RNA has an U instead of a T ACA and UGU are codon or trinucleotide sequences of DNA or RNA respectively.

https://www.uwa.edu.au/science/-/media/Faculties/Science/Docs/Protein-synthesis-summary .pdf Amino acids, Peptides & Proteins - Proteins are large biomolecules that occur in every living organism. - Many different types - Many biological functions - Eg.: - Structural proteins (collagen, keratin) - Protective proteins (venoms, blood-clotting proteins, antibodies) - Enzymes (proteins that catalyse the reactions that occur in living systems) - Hormones (eg. Insulin, which regulates glucose metabolism) - Proteins with physiological functions (eg. hameoglobin) - Regardless of their appearance or function, all proteins are chemically similar. - All are made up of many amino acid units linked together by amide bonds in a long chain. α-Amino Acids - Building blocks for peptides and proteins:

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α: Location of the amino group relative to the carboxylic acid. Ionic compounds normally.

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Can behave as acid or base depending on pH of soln.

Side Chains - The amino acids differ only in the substituent (R group) attached to the α-carbon. - The wide variation in these substituents = Side chains - Is what gives proteins their great structural diversity and as a consequence, their great functional diversity. - Common names are almost always used. - Glycine (from Greek glykos - sweet) - Asparagine (first isolated from asparagus) - There are 20 common amino acids encountered in peptides and proteins. - Ten of these are essential amino acids - these must be obtained from our diet. - The amino acids can be classified according to their properties, which are dictated by the type of side chains attached, e.g.: hydrophobic, hydrophilic, acidic and basic. Peptides Can combine two amino acids to form a peptide:

Proteins are polypeptides that usually contain > 100 amino acid residue

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By convention, the sequence of amino acids in a peptides (or protein) is always written from the N-terminus (on the left) to the C-terminus (on the right). Naming

Dipeptides - One possible dipeptide from two identical amino acids. - For different amino acids: (# of amino acids)^2 Tripeptides - Formula: (# of different amino acids)^3 - This structural diversity can provide the complexity required for structure and function in nature. - If we have a protein that consists of 100 amino acid residues, there are 20^100 possible structures. - Sickle cell anaemia is a condition that is caused by a change in shape of hemoglobin due to substitution of a valine residue by glutamic acid. Shape & Structures of Proteins - Amide bonds are planar:

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This has an important influence on the structure of proteins as the partial double bond character of the amide bond also has stereoisomeric consequences.

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Proteins have a specific 3D shape. This is determined by: - Sequence of the amino acids (primary structure). - Folding of the primary structure into domains such as α-helices and β-sheets (secondary structure). - Additional intra-chain interactions such as hydrogen bonding btw. amide groups/side-chain groups and covalent bonds such as disulfide links (tertiary structure).

Carboxypeptidase A

α-Helix - Structure - coiling of the polypeptide backbone around the long axis of the protein molecule - L-amino acids generate a right-handed helix with 3.6 residues per turn and a repeat distance of 5.4 Å. - Steric hindrance (a) - R groups protrude outward to minimize steric clashing. - Hydrogen bonding (b) - intrastrand - carbonyl oxygen of one amino acid residue and the amide hydrogen of another 4 residues away.

β-Sheet - Structure: the polypeptide backbone forms an extended zigzag structure resembling a series of pleats - a repeat distance of nearly 7 Å, strands average ~6 residues, and sheets average 2-15 strands.

Contributors to Tertiary Structure - Tertiary structure: Proteins fold spontaneously in solution to maximize their stability every time there is a stabilizing interaction between two atoms, free energy is released (large negative ∆G = stable protein). - Proteins will fold in a way that exposes the maximum number of polar groups to water and buries the non-polar groups in the protein’s interior.

Quaternary Structure - The quaternary structure refers to the number and arrangement of the protein subunits with respect to one another. - Quaternary structure exists in proteins consisting of two or more identical or different polypeptide chains (subunits). These proteins are called oligomers because they have two or more subunits. The quaternary structure describes the manner in which subunits are arranged in the native protein - Protein structure: Quaternary structure - 3D arrangement of individual peptides within a multisubunit protein.

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Hemoglobin: tetrameric protein made up of two different kinds of subunits.

Drug Action At Proteins - Drugs interact with a variety of proteins - Enzymes (body’s catalysts). - Receptors (body’s letter boxes - crucial -

to communication btw. cells). Carrier proteins (in the cell membrane and they transport chemicals into and out of the cell. Structural proteins (not a normal target but tubulin is an important exception).

The Drug Discovery Process

Aspirin - Aspirin is excellent at lowering dangerously high fevers  these arise due to elevated levels of PGE2 in the brain - PGE2 is beneficial in the stomach as it inhibits excessive production of HCl and helps with the formation of a protective mucus layer - Aspirin has excellent anti-clotting properties (80-90 mg/day) - Lowers risk of heart attack - Limits brain damage - This activity is the result of aspirin causing the irreversible inhibition of COX in blood platelets. - The mature platelets have a lifespan of just 2 weeks and are unable to synthesise new protein, so platelets treated with aspirin are permanently blocked - Interferes with an enzyme that makes prostaglandins, leukotrienes and thromboxanes. Prostaglandins - class of compounds responsible for regulating a variety of physiological responses: - Inflammation, blood pressure, clotting, fever, pain, induction of labor, sleep-wake cycle Thromboxanes - constricts blood vessels and stimulates the aggregation of platelets (first steps of blood clotting) Prostacyclins - dilates blood vessels and inhibits platelet aggregation Arachidonic acid - precursor - Arachidonic acid is the precursor to the prostaglandins, leukotrienes and thromboxanes. - They are made in the arachidonic acid cascade. - The enzyme that catalyses this transformation is known as CYCLOOXGENASE (COX). Pain relief - reduce prostaglandin synthesis by inhibition of cyclooxygenase activity Aspirin acetylsalicylic acid - acetylation of a critical serine residue inactivates the enzyme Aspirin also slightly reduces the synthesis of thromboxanes and prostacyclins causing a slight decrease in the rate of blood clotting - preventive treatment for heart attack and stroke caused by clotting in blood vessels

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These NSAIDs (nonsteroidal anti-inflammatory drugs) inhibit the synthesis of normal physiological prostaglandins, as well as those produced in response to inflammation side-effects Regulation of acid production in the stomach interference can elevate acid levels in the stomach leading to stomach irritation

What causes analgesia?  Nerve transmission is dependent on ions flowing into and out of a nerve cell  Opening or closing ion channels will disrupt nerve transmission  Morphine binds to a receptor that activates an ion channel and allows potassium ions to flow out of the nerve cell  This hyperpolarizes the cell and an action potential cannot be propagated  This also causes fewer calcium ions to flow into the cell which reduces neurotransmitter release

Common structural features

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Morphine and all of the compounds prepared by molecular modification have a common structural feature.

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An aromatic ring attached to a carbon that is attached to a tertiary amine two carbons away

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Alternative splicing: A mechanism by which different forms of mature mRNAs (messengers RNAs) are generated from the same gene. Alternative splicing is a regulatory mechanism by which variations in the incorporation of the exons, or coding regions, into mRNA leads to the production of more than one related protein, or isoform. Alternative splicing is a fundamental regulatory process of gene expression. Defects in alternative splicing can lead to various diseases, and modification of disease-causing splicing events presents great therapeutic promise. Splicing outcome is commonly affected by extracellular stimuli and signaling cascades that converge on RNA-binding splicing regulators. Alternative splicing is the process of selecting different combinations of splice sites within a messenger RNA precursor (pre-mRNA) to produce variably spliced mRNAs. These multiple mRNAs can encode proteins that vary in their sequence and activity, and yet arise from a single gene. Alternative splicing is an important mechanism in the developmental and cell-type specific control of gene expression, and as a mechanism for increasing the proteome diversity. It is found in nearly all eukaryotic organisms that carry out standard nuclear pre-mRNA splicing, including animals, plants, and, in some cases, fungi. Alternative splicing is modulated by many proteins which interact with a large array of splicing enhancer and splicing suppressor sequences.

Side chain polar charged/non polar charged/h Hydrophobic = Carbons + hydrogen Hydrphillic = Anything else + carbon + charged ( Acidic = -, basic = +)...