Summary study book an introduction to medicinal chemistry of Graham Patrick (H1,2,3,4,5,8,10,21) - ISBN: 9780199697397, Edition: 5e druk, Year of publication: -
H1
Drug = to design and synthesize a pharmaceutical agent that has a desired biological effect on the human body
or other living systems.
Therapeutic index indicates how safe a drug is
Macromolecules are large molecules
Intermolecular bonds are a weaker form of interactions:
Electrostatic/ionic bonds is the strongest of intermolecular bonds (opposites attract)
Hydrogen bonds (H-bruggen) these bonds vary in strength. There are hydrogen bond donors (HBD
has to contain electrodeficient proton linked to oxygen/nitrogen), which provide hydrogen for
hydrogen bond. There are hydrogen bond acceptors (HBA has to be electronegative), which provide
the electron-rich atom to receive the hydrogen bond. OH and NH 2 are both HBA and HBD (=hydrogen
bond flip-flop)
Van der Waals interactions very weak form of interaction. It takes place between non-polar regions
of molecules and is caused by transient dipole-dipole interactions. VdWaals interactions are crucial to
binding because the interactions may be individually weak, but there may be many such interactions
between a drug and its target.
Dipole-dipole interactions strength of interactions reduces with the cube of the distance between
two dipoles
Hydrophobic
None of these bonds is as strong as a covalent bond, which makes up the skeleton of a molecule
Pharmacodynamics = the study of how drugs interact with their targets through binding interactions and
produce a pharmacological effect
Pharmacokinetics = the study of how a drug is absorbed, distributed, metabolized and excreted (ADME)
Proteomics = the study of the structure and function of novel proteins discovered through genomics
4 classifications of drugs:
1. Pharmacological effect
2. Chemical structure
3. Target system
4. Target molecule
H2
1. Primary structure = the order in which the individual amino acids making up the protein are linked
together through peptide bonds
2. Secondary structure = consist regions of ordered structure adapted by the protein chain. It had 3 main
structures:
α-helix
β-pleated sheet = a layering of protein chains one on top another
, β-turn allows the polypeptide chain to turn abruptly and go in the opposite
direction. It is important in allowing the protein to adopt a more globular
compact shape
3. Tertiary structure = the overall three-dimensional shape of a protein. The bonding interactions here
are the same as intermolecular bonds.
4. Quaternary structure = proteins that are made up of a number of subunits
Van der Waals interactions is the most important bonding:
In most proteins there are more possible opportunities for VdWaals en hydrogen bonds than
covalent/ionic bonds
Proteins are surrounded by water water is a highly polar compound that interacts with polar,
hydrophobic amino acid residues
Enzymes contain a hollow or canyon active site. It protrudes into the centre of the protein, which is
hydrophobic and can provide a non-aqueous environment for reaction
Translation = a process by which a protein is synthesized in the cell. Some proteins are cleaved into smaller
proteins or peptides following translation
Protein functions as drug targets:
Structural proteins polymerize to form small tubes (microtubules) in cell cytoplasm, this is crucial to
cell division. Example: tubulin
Transport proteins these proteins smuggle the important chemical building blocks of amino acids,
sugars, and nucleic acids across the cell membrane, so the cell can synthesize its proteins,
carbohydrates and nucleic acids. And also transport neurotransmitters into neurons
Enzymes and receptors
Miscellaneous proteins and protein-protein interactions
H3
Enzymes are proteins, which act as the body’s catalysts agents that's speed up a chemical reaction without
being consumed themselves.
Activations energy = the difference in energy between transition state and substrate. This is lowered by an
enzyme.
Factors enzymes:
Enzymes provide a reaction surface and a suitable environment
Enzymes bring reactants together and position them correctly so that they easily attain their transition
conformation
Enzymes weaken bonds in reactants
Enzymes may participate in the reaction mechanism
Enzymes form stronger interactions with the transition state than with the substrate/product
Amino acids functions:
Binding binding the substrate of cofactor to the active site
Catalytic
Koshland’s Theory of Induces Fit = a theory that substrate induces the active site to take up the ideal shape to
accommodate it.
, Acid/base catalysis provided by amino acids, histidine, glutamic acid, aspartic acid and tyrosine (acts as proton
source).
Amino acids serine and cysteine act as nucleophiles in the reaction mechanism of some enzymes. In some
enzymes, cysine can act as nucleophile.
Many enzymes require additional non-protein substrates called cofactors; these are metal ions or small organic
molecules (=coenzymes).
Coenzymes are bound by ionic bond or non-covalent bonding
Genetic polymorphism = a difference of one base pair in every 1000 between individuals.
Allosteric = a binding site separate from the active site
Why bind to allosteric, if there’s an active site?
It alters the shape of the enzyme so that the active site is no longer recognizable
Binding final product to the active site is not a very efficient method of feedback control
Allosteric inhibitors are involved in the feedback control of biosynthetic pathways
External control involves regulation initiated by a chemical messenger from outside cell phosphorylation
Iso-enzymes = a variations of same enzymes. Catalyse same reaction, but differ in primary structure, substrate
specifity and tissue distribution.
The Michaelis-Menton equation relates the rate of an enzyme-catalysed reaction to substrate concentration.
The Michaelis constant is equal to the substrate concentration at which the rate of the enzyme-catalysed
reaction is half of its maximum value.
H4
Neurotransmitters and hormones don't undergo a reaction when binding to a receptor. The depart unchanged
once they’ve delivered their message.
Three types of membrane-bound receptors:
Ion channel receptor. Glycoproteins = the 5 protein subunits that make up an ion channel.
G-protein-coupled receptor (GPCR). GPCR activates G-proteins. Binding of a messenger results in the
opening of a binding site for signal protein, this binds and fragments with one of the subunits
departing to activate a membrane bound enzyme. G-proteins are also called 7-TM receptor, because
of their number of transmembrane regions.
C-terminal chain lies within cell, but N-terminal chain is extracellular.
Kinase linked receptor activate enzymes directly, don't need G-proteins.
Messenger binds kinase active site opens catalytic reaction
Example: tyrosine kinase receptors. They have extracellular binding site and intracellular enzymatic
active site catalyses the phosphorylation of tyrosine.
H6
G-proteins are made up of three protein subunits:
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