new trends // targets
targeting protein protein interactions that were considered undruggable
lipinskis rule is whattt
a rule of thumb!!
also a rule of 5 🤞🏼
getting violated by many newish drugs that are large complex natural products
why the 5 lipinskis rules
drug discovery companies limit themselves to these rules as small molecules that violate these rules tend to be too toxic in general
name the 5 lipinski rules
- no more than 5 H bond donors in a molecule
- no more that 10 H bond acceptors in the molecule (O + Ns in total)
- molecular mass less than 500amu
- octanol // water partition coefficient (Clog P) that does not exceed 5)
molecules that obey lipinskis rule are said to be
‘druglike’
name some biologics
proteins
hormones
antibodies
vaccines
gene therapy (vaccines)
recombinant proteins
insulin hormone
controls glucose absorption from blood
what leads to autoimmune diseases
over activity of the immune system can lead to autoimmune disorders
name some autoimmune disorders
- rheumatoid arthritis
- psoriasis
- asthma
- hay fever
- crohn’s disease
what triggers an immune response
an antigen
killer cells in an immune response
a phagocyte
non specific
what is inflammation caused by
release of cytokines
from macrophages
in order to reduce damage from trauma
what is a cytokine
small signalling proteins secreted by certain cells of the immune + nervous system
what do cytokines activate
an immune response + inflammation
cytokine timeline ig
recognised by specific receptors on cell surfaces
the cytokine - receptor recognition system is targeted to suppress inflammatory diseases.
acute phase reaction
cytokine production by macrophages
inflammation
structure of an antibody
- variable region / portion
- constant region / portion
- light chain (outer + shorter)
- heavy chain (inner + longer)
- disulphide bond between heavy and light chain.
polyclonal
different antibodies being produced by different b cells//leukocytes during an immune response to produce a large variety of binding regions // variable regions.
antibody that comes from one b cell only
monoclonal antibody!!
same variable portion
why are polyclonal antibodies not rlly good at inhibiting specific disease
they have different variable regions
therefore different effects
they therefore have unpredictable + inefficient pharmacological effects
what are problems with monoclonal antibody production
- cells undergo apoptosis + die after 50 divisions : need a cell that grows indefinitely
- need to grow many IC in order to find effective antibodies
- variable region must be human to target human cells.
- constant region should be part animal,, variable region should be part human. this is bc human immune system recognised the heavy chain + led to an immune effect (part human part animal). ANTIBODY SHOULD BE CHIMERAS (part human and part animal)
chimeras
antibody is split
- variable region + human
- constant region + animal
bc constant regions,, if human can be recognised by the human immune system + trigger an immune response
monoclonal antibody production
- mouse immunised by antigen + it’s spleen produces plasma cells that secrete specific antibodies
- myeloma cells that can’t product antibodies are selected
- plasma cells from spleen and myeloma cells fuse -> hybridomas.
- infused cells die
- cell transferred to a medium
- hybridomas (plasma X myeloma) are bulk grown (it selected)
how many of the top 10 best selling drugs are small molecules
only 2 of the top 10!! m
eliquis
biktarvy
