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Printable Handouts
Navigable Slide Index
- Introduction
- Protein family size: a significant opportunity
- GPCRs as drug targets
- It's a GPCR world?
- A GPCR world? - 2012 FDA approvals
- Why a reduction in GPCR drugs?
- AstraZeneca target screening success
- GPCRs have liabilities associated with them
- Have we picked all the low hanging fruit?
- GPCRs continuing to shape drug discovery
- There remain 140 nonolfactory orphan GPCRs
- New screening and pairing publications
- New technologies
- Commercially available screening technologies
- 120 years of research
- Now there are many different GPCR structures
- Examples of fragment based screening
- Companies that targets GCPRs
- Understanding of ligand receptor binding sites
- Facilitating allosteric modulator approaches
- Multiple binding pockets in family A receptors
- Intracellular binding pockets in family A
- Example of intracellular allosteric binding site
- How can we exploit these for drug discovery?
- Impact: marketed products and company focus
- We are also learning about GPCR signaling
- How the GPCR diagram looks today
- Ligand biased signaling
- Compounds in G-protein and beta-arrestin paths
- Dynamic mass redistribution and pathway assays
- Splice variants can modulate coupling
- Better drugs based on ligand bias knowledge
- Example for a drug based on ligand bias
- Opportunities for new drugs at validated targets
- Combining allosterism with ligand bias (1)
- 6 ligands with different signaling properties
- BETP a positive modulator of oxyntomodulin?
- BETP negative allosteric modulator of GLP-1?
- Combining allosterism with ligand bias (2)
- A simple picture can become complicated
- Acknowledgements
Topics Covered
- The G-protein coupled receptor superfamily
- GPCRs as drug targets
- Approved GPCR drugs
- why the reduction in GPCR drugs
- new screening technologies and new drug targets
Talk Citation
Wigglesworth, M. (2014, February 4). G-Protein coupled receptors in drug discovery [Video file]. In The Biomedical & Life Sciences Collection, Henry Stewart Talks. Retrieved October 12, 2024, from https://doi.org/10.69645/TUOC7432.Export Citation (RIS)
Publication History
Financial Disclosures
- Dr. Mark Wigglesworth has not informed HSTalks of any commercial/financial relationship that it is appropriate to disclose.
A selection of talks on Biochemistry
Transcript
Please wait while the transcript is being prepared...
0:00
Hello, and welcome to the Henry Stewart
lecture series on Small
Molecule Drug Discovery.
My name is Mark Wigglesworth, and
I'm the Director at the Global High
Throughput Screening
organization within AstraZeneca.
Today I have a
presentation for you on,
G-Protein Coupled Receptors
in Drug Discovery.
I've had a long interest
in both screening
and in G-protein coupled receptors.
I hope the presentation that
follows will give you some insight
into both and how their
impacting to discovery
both today and in the future.
0:36
I'm going to start with some
information which I'm sure you're
all already aware of,
and that is GPCRs,
the size of the super family,
and that this is actually
a very significant
opportunity for all
of us that work
within drug discovery.
The graph that you're
looking at on this slide
simply shows the number of proteins
targets within some major target
super families.
And GPCR showed, on this graph, as
having around 800 family members,
by far the largest single
protein class that are
successfully targeted
by drugs today.
1:17
And as drug targets, GPCRs are
involved in almost all diseases
throughout the human body.
Perhaps more importantly for
drug discovery, of course,
is that this family
of proteins are highly
tractable and highly profitable.
They are the most exploited
class of drug targets,
with approximately 36% of
all drugs targeting them.
And just taking a moment
to think about that,
that's quite phenomenal.
The effects that this target
class and drugs acting upon them
has had on human health
historically is very significant.
Indeed, according to
data from IMS Health,
six out of the top 20 drugs in
terms of global sales in 2010,
targeted GPCRs.
That is 30%.