Professor Robin Leatherbarrow
Head of Biological Chemistry
Department of Chemistry
• Modulates a specific biological process
• Enzyme inhibitor

Reversible competitive inhibitor
• e.g. Viagra

Irreversible enzyme inhibitor
• e.g. Penicillin, aspirin
• Small molecular weight compound

Obeys Lipinski “rule of 5”
• Less than 500 molecular weight etc

Orally available
Enzyme with a
defined substratebinding site
Substrate binds
and is converted to
product(s)
Inhibitor blocks
substrate binding
Enzyme
P
Protein responsible
for biological effect
Effect modulated
by protein-protein
interaction
Inhibitor regulates
effect by blocking
protein-protein
interaction
Protein
1
I Protein
2
Human genome: 30,000 drug targets
Disease-related
targets:  10%
Figures from Hopkins and Groom (2002) Nature Rev Drug Disc 1, 727
Druggable
20-50%
Undruggable
50-80%
• Account for the majority of biological control
points
• Are implicated in all areas of medicine


Wide ranging impact
Many therapeutic areas
• …BUT ARE DIFFICULT TO TARGET
Typical Enzyme-Substrate Interaction
Typical Protein-Protein Interaction
Well-defined binding pocket
Relatively flat surface
Relatively small contact area (300-1000
Å2 )
Relatively large contact area (1500-3000
Å2 )
Intrinsic interaction is relatively weak, so
easy to block
Intrinsic interaction is relatively strong…
Screening involves looking for compounds No enzyme assay for easy screening
Protein 1
Protein 2
that affect enzyme activity—assay is easy
Enzyme
S
Substrate structure gives “clues” towards
inhibitor design
No such information available
Inhibitors the size of the substrate are still
likely to be small (Rule of 5 compliant)
Inhibitors of comparable size to the
interacting surface will be too large
There are MANY examples of successful
drugs that target enzymes
There are VERY FEW examples of any
drugs that target Protein-Protein
interactions
• There are a few examples of successful drug
leads that are targeted at Protein-Protein
interfaces
• However, there are currently NO marketed
drugs that work this way…
Review: Wells & McClendon (2007) Nature 450, 1001
• B-cell lymphoma (Bcl) 2 family proteins are
important regulators of apoptotic cell death
and form homodimers with other family
members
Bcl-XL (grey) bound to partner
protein via alpha helical region
Bound small molecule inhibitor of
this interaction
• Interleukin-2 is a cytokine that has a key role
in activation of T cells and in the rejection of
tissue grafts, by binding to IL-2 receptor
IL-2 (grey) bound to partner
protein
Bound small molecule inhibitor of
this interaction
• Human papilloma virus (HPV) causes warts
and some cervical cancers. The interaction
between HPV transcription factor E2 and
helicase E1 is vital for the viral life cycle
HPC E2 (grey) bound to EPV E1
Bound small molecule inhibitor of
this interaction
• Where do we start?



Fragment screening?
Peptidomimetic approaches?
Allosteric modulation?
• How do we assay?

Throughput / sensitivity?
• How do we optimise leads?

Starting points not “drug-like”?
Trypsin
Interacting
region
Protease
Synthetic
interacting motif
Trypsin Inhibitor
Protein (BBI)
Ki = 9 nM
• Discrete liquid droplets
are encapsulated by a
carrier fluid
• Droplets:



are isolated and form the
dispersed phase in which
reactions may occur
can be dosed with
varying amounts of input
reagents
can be generated at kHz
frequencies
Andrew de Mello, Imperial College
• Angiogenin – antiAngiogenin
1.0
0.8
EFRET
0.6
0.4
KD = 6.4 nM
0.2
0.0
0
20
40
ANG-AF647 (nM)
60
Monpichar Srisa-Art, Dong-Ku Kang, Jongin Hong, Hyun Park, Robin J. Leatherbarrow, Joshua B. Edel, Soo-Ik Chang, and Andrew J. deMello; ChemBioChem 2009
• Protein-protein interactions are potentially
extremely useful drug targets
• They are far more difficult than “traditional”
drug targets
• They offer new therapeutic possibilities that
should become exploited in coming years