lect 2 Flashcards
Biological molecules are modular b/c
- b/c they can easily assemble and disassemble for reuse complex structures
only 1 enzyme is need for each biomolecular type and function listed below
o Shape and density determine binding (noncovalent interactions—ionicdissociation//>solubility in a 3D way for a drug and biomolecule)
Can be covalent after bonding
proteins are…
linear chain of amino acids held by amide bonds
o Made by ribosome
o Disassemble by proteasome
o Drug comes into effect by binding to bio molecules
Drug binds to substrate modification response (universal)
nucleic acids are…
linear chain of nucleotides held by phosphate esters
polysaccharides are…
linear chains of sugars, some are branched and held by acetals
lipids are…
linear chains of acetate or propionate whose assembly units are hidden held by aldol
how do proteins differ from each other and how are they the same
- 20 AA that have the same backbone and stereochemistry (R groups are hashed)
o Differ from their side chains ‘R’
o Special AA: glycine and proline—no side chain, affects rotation)
Primary structure of Proteins
- Seq of AA from n terminus (nitrogen) to c terminus (carboxylic)
Secondary structure of Proteins
- Local order in the backbone
- Helix
o Ribbon
o H bonding b/w peptide bonds - Beta strand
o Same plane, flat paper=sheet
Strands can associate together
Large sheets curl around themselves forming cylinders= BARREL
H bonds hold sheet together
Parallel or antiparallel
- Loops
o No defined secondary structure
o Spaghetti on ribbon diagrams
- Turns
o Chain changes direction by a large amount
o Connect secondary structure elements
how does Conformational and chiral centres restrict rotations in amide bonds (amide and alpha carbon)
o Intermolecular forces acting intramolecularly causing structure to fold
o Amide chooses s-trans b/c its more stable—no steric interference
o Side chains—hydrogen bonding with backbones, nonpolar side interact with other nonpolar chains= folding
tertiary structures
- Overall 3D shape of protein = secondary structures combined
- Nonadjacent regions interact
o AA side chains
o 2 secondary structures
Causes secondary structures to fall back on themselves
Noncovalent bonds
quaternary structure
- 2+ proteins bind together e.g. Hb
- Subunits can be same or diff
- Protein-protein interactions
o Strong
o Chem rxns
o Surface area
o Expulsion of water
o They stick tightly
attraction forces in tertiary structures
o Disulfide covalent bond b/w AA
o Ionic bonding
o Hydrogen bonding
o Van der Waals
Polar side chains outside of protein
Nonpolar inside of protein
* Holds protein together
* Dipoles and H bonding weaker in water but are stronger in nonpolar environment
o Protein dissociates in water but remains in nonpolar environ slide41
protein shape
Structure=function
* Most of the protein is a scaffold to hold everything together in the correct shape
* Small part is functional
protein target for drugs
enzymes
receptors
ion channels
structural proteins
enzymes
o Drug stop enzymes from working
receptors
o Activate (agonist) deactivate (antagonist) the receptor
o May do both
ion channel
o Open/close the channel
structural protein
o Interfere with assembly/disassembly of protein structures
enzymes catalyze rxns by
providing a designed environment for the transition state of a reaction
o Enzymes bind tightly to transition states (dec in activation energy)
o Enzyme trans state product (reversible)
* Enzyme active site is small the rest is for support
* Active site chemistry is complimentary to trans state
* Enzyme binds to substrate
o Both change shape to get an induced fit
o Substrate is converted into product and is released (change in shape)
Can be done by lock and key (sub. Is exact shape as enzyme)
Induced fit (conform. Change activates and deactivates enzyme)
inhibitions
competitive, non competitive, uncompetitive, irreversible
competiive
o Inhibitor fights w/ substrate for active site
o Disulfiram (Antabuse)
Blocks acetaldehyde dehydrogenase and produces a hangover
at 1 but steeper
noncompetitive
o Inhibitor binds elsewhere from the active site
Prevents trans state from forming since it alters the shape of the enzyme
o Substrate binds to active site
o fluconazole
no longer at 1 and steep
uncompetiive
o Inhibitor binds to trans state
Destroys catalytic ability of trans state
Lithium
not at 1 but parallel to slope at 1 b/c equilibrium of ES and I
irreverisble
o Covalent inhibitors
o Bond covalently to enzyme active site
o Alt conformations or disabling f’nal groups
o Bond on active site
o Penicillin
recpetors binding…
o Chem interactions b/w messenger (ligand) and receptor, changes shape of receptor
o Conformational change allows 2nd messenger to bind or release
Agonist binding allows shape change that result in a signal
Bind at active site as messenger
Some agonists bind at diff locations (allosteric sites)
receptors catalysis
o Chem interactions b/w messenger (ligand) and receptor, changes shape of receptor
o Shape change allows the creation or destruction of catalytic function
agonist stimulate messenger
- Agonists activate receptor and replaces messenger; binding induces shape change that results in transmission of a signal
o Bind at same location
o Some bind at other sites (allosteric)
o Asthma drugs are adrenaline agonist
Adrenaline receptors in lungs stimulate bronchial opening when activated
Bind to active site of noradrenaline receptor
alloesteric modulators
*indirectly influence or modulate the effects of an agonist at a receptor
Benzodiazepines
o GABA is an inhibitory NT
o In its presence channels opens more readily and stays open longer
antagonist
- Binding induces abnormal shape change those results in no signal transmission
- May bind at same location or other sites
o Tagamet is an active site antagonist (turns off stomach acid)
Binda to a histamine binding site (produces stomach acid)
Distance b/w main binding domains larger than histamine
allosteric antagonist
- Can bind near or partly inside of active site or distal location
- No longer able to bind to messenger
partial agonist
- Agonist binds to receptor and produces non-ideal conformational change
o Weak signal is sent
o Enzyme wont be on long enough (bind weakly = weak reception)
One binding gives agonism the other antagonism - Buprenorphine (used to block the effects of opioid poisoning)
inverse agonist
- Receptor gives weak signal to bind to messenger and then there’s an increase in strength of the signal
antagonizes the effects of an agonist but, moreover, exerts the opposite effect by suppressing spontaneous receptor signaling - Clozapine shows inverse agonist behaviour
measuring drug behaviour
- Use biological assay (how fast cell grow)
- Qualitative (number)—how well it works
- In vitro
o Using bio chemicals, cells or tissues
o Always preferred easier and cheaper - In vivo
o Tests done in living animals
general assay types
HPTS
routine SARS
* Kinetics or special studies
o Quantitative
* Cell based
o Antibiotics, antivirals, anti-cancer, metabolism studies
o Result of several properties
* Tissue based
o Permeability and complex
