Drug action Flashcards
(40 cards)
types of receptors
enzymes, GPCRs, VGIC, LGIC, carriers, transporters
receptors as drug targets
1/3 of drugs target receptors
1000 receptor proteins
several binding sites, bind ligands and release unchanged
trends in indications
analgesics constant
diabetes drug increasing, plus alzheimers and obesity
trends in classes of target
growing in ligands and serine/RTKs
LGIC already found lots of targets
lots of GPCRs unexplored (100/400 non-olfactory) - orphan
orphan GPCRs
not matched to endogenous ligand
trends in molecule type
small molecules are more common moving more diverse - proteins, peptides, antibodies, etc
tends in mode of action
antagonists and agonists common moving to positive/negative allosteric modulator and biased drugs
allosteric modulator
bind elsewhere on receptor to change response to orthosteric ligand
can be more specific to one receptor subtype = more diverse
biased ligands
agonist -> unique conformation of receptor -> activate only certain signalling molecules
fewer side effects
eg opioid -> don’t activate arresting, only g protein
future of drug discovery
robust target validation (cause and causation)
better understanding of pharmacological targets
broad view of potential targets, molecule types, modes of action
allosteric agonist
bind allosterically and directly activate/inactivate the receptor
proteins
catalysts, receptors, scaffolding, transport, communication
proteins as drugs
cannot mimic with simple chemicals
less potential to interfere with normal biological processes
well tolerated, no immune response
replace deficient or abnormal protein, augment existing pathway
making protein biologics
PCR -> select vector -> recombinant vector -> organism -> selection and sequencing -> expression -> purify
production systems
bacteria, yeast, mammalian cells, transgenic animals
consider cost and PTMs
interferons
produced by any cell in response to virus infection
activates antiviral response and stops spread
recombinant interferons
produce in mammalian cells for glycosylation
coagulation to polyethylene glycol and glycoengineering to improve Vd, clearance and half life
inject into body for viral clearance/milder disease
monoclonal antibodies
antibody made from cloning a unique white blood cell to substitute antibodies
interfere with growth factors, inflammatory cytokines, immune cells
deliver compounds and proteins
interferons vs antibodies
antigens stimulate production of antibodies from B cells -> remove antigen
interferons are antiviral glycoproteins released by cells under viral attack -> viral resistance
antibodies
proteins produced by immune cells in response to foreign antigens (microbes, human proteins or cells)
antigen detected by T cell -> activate B cells -> clone plasma cells -> secreted antibodies
bind to block antigens action
making monoclonal antibodies
take B cells from animals and grow to find best via Fc domain (hybridoma)
use phage display (screening for best binding)
transgenic mice with human immune cells (screen B cells)
remove human B cells -> production of cell lines
chimeric and humanised
chimeric - clone variable domain (-ximab)
humanised - take antigen recognition domain (-zumab)
or recombinant
biologics examples
tumor necrosis factor - cytokine produced for tissue damage/infection -> cell death, inflammation etc.
anti-TNF (covid) monoclonal antibodies - humanised adalimumab (less immunogenic)
biologics challenges
complex to make, difficult to deliver, have multiple effects and are expensive to use
