Drug Discovery: Reductionism v Complexity
Elrig Drug Discovery conference 2018
Steven Zimmer
CEO
MitoDys and EpiCombiTherapeutics
Brief Bio
• Biochemist/Molecular Biologist
• Long career as an Analyst, Investment Banker, Portfolio Manager
• Visiting researcher SGC, Oxford University
• Rare Disease Consortium Oxford
• Biotech Entrepreneur
• Protein Sciences (sold to Sanofi 2017)
• MitoDys Therapeutics
• EpiCombi Therapeutics
• Others!
Why are we here?
Alleviate suffering and reduce mortality….right?
Have we really been successful?
To a degree we have…but…
All of the low hanging fruit has been picked!
Left with…highly complex intractable multi-factorial diseases
Cause significant morbidity and early mortality
However….Drug discovery is stuck
Why is drug discovery stuck?
Absolutely obsessed with targets
…pathologically so!!
Reduction to a target is the be all end all
When it does not work (96% of the time!!)…
Supposedly…Need better targets
And on and on and on and on…..
Is this really the way that biology works?
This is what I learned!
TCA/Kreb Cycle
ACTUALLY…
Reality Check!!!
The Internet
Ecological Network
Biological Networks
Built to be robust
Fault-Tolerant
Modular and interconnected
Are so through:
• Ability to Adapt
• Crosstalk and feedback loops
• Redundancies/Alternate functional paths
Single Target???????
Biology: Interaction network of modules.
Luo F et al. Bioinformatics 2007;23:207-214
Disease: Multi-factorial complexity
• It gets worse!!!
• Breakdown of cellular functionality/failure of multiple systems
• Multi cell-type dysfunction
• Genes
• Immune system interactions
• Epigenetic drivers
• Multiple RNA types
• Post-translational modifications
• ….etc…etc….etc.
• In other words….its a….!
To make things even worse…
Drug promiscuity
How to harness this…
To deal with that?
Hierarchical Clustering
Gluccocorticoids
Benzodiazepenes
Estrogenics
MAO inhibitors
Opiates
Anticholinergics
Beta blockers
Antipsychotics,
SSRIs,Tricyclics
etc.
NSAIDs
I15
I10
I04
E32
E12
E04
I13
R26
R91
R62
E09
I12
E25
I08
R55
I11
E18
E22
E31
I02
R16
I07
R82
R12
E14
E27
I05
I14
R24
E07
E11
R75
R29
R38
R47
R90
I01
R15
R01
R63
R89
R28
R51
R84
T05
T04
R17
R60
R22
R43
R19
R27
R39
R18
R21
R88
R44
I03
R13
I06
R78
R72
R14
R02
T02
Hierarchical Clustering
Gluccocorticoids
Benzodiazepenes
Estrogenics
MAO inhibitors
Opiates
Anticholinergics
Beta blockers
Antipsychotics,
SSRIs,Tricyclics
etc.
NSAIDs
I15
I10
I04
E32
E12
E04
I13
R26
R91
R62
E09
I12
E25
I08
R55
I11
E18
E22
E31
I02
R16
I07
R82
R12
E14
E27
I05
I14
R24
E07
E11
R75
R29
R38
R47
R90
I01
R15
R01
R63
R89
R28
R51
R84
T05
T04
R17
R60
R22
R43
R19
R27
R39
R18
R21
R88
R44
I03
R13
I06
R78
R72
R14
R02
T02
Biological ComplexityNetworks
Fault ToleranceRedundancies
Plasticity...
Drug Promiscuity
Targeted???Never!
Proteins
Dru
gs
Single Target???Where?
Biology & Drugs: Complexity & Single Targets
Drug promiscuity
What to do????
1Tie a cement block to
your foot and jump into the dock water outside
or…Commit Seppuku in front
of the Excel Centre
2Take one of the happy
pills I left in a box outside the hall
This is a drug discovery conference after all!
3Listen to what I have to
say next…
Solutions:Data
• A Galaxy of Data!!!
• Omics of all sorts (Genomic, Proteomic, Methylomic, Metabolomic….)
• RNA
• Sequencing/Genetic
• Clinical
• Chemical
• Chemical Biological
• Pharmacological
• Genetics
• And so on…
Solutions:Analytics
Accessible Public Datasets
Inaccessible Pharma/Biotech data
Plethora of Analytical tools
Ability to create new ones
Invent new ways of combining data
How do we apply this to Drug Discovery?
Think Differently
• System
• Biological mechanisms
• Modification of phenotype
• How to dissect disease biology and link it to pharmacology and drugs?
How do I think? Signatures
Omics and
chemical data
Using:
•Current pharmacopeia,
•Failed/discontinued drugs
•High quality chemical probes
Generate prototype
drugs (single or
combination) to test
Use Machine Learning to train
this data to predict patterns
Identify further
prototype drugs to
test
Polypharmacology…what a mess…or…
• Phenotypic change and Biomarkers identified
• Biological tools to manipulate
• Identify active components
• Use to construct single compounds with dual activity or
• Formulated combinations with known compounds
Deconvolution to the
essentials
Lessons to learn
Remember….this is about patients!!!
Change must come to achieve greater productivity and success
Emerging paradigm: network and systems pharmacology
Extraordinarily disruptive in Pharma/Biotech context
The whole system is geared to oppose this
While it is easier to simplify things…it generates costly errors
Prevailing Reductionist paradigm is broken
Paul Ehrlich’s Magic Bullit is not relevant anymore
We know so much more than he did!!!
Conclusions
Much more to say
Not about dissing medicinal chemists and conventional pharmacology
Provoke thought and discussion
Knowledge and Tools
Use them for the right purpose
Heart wrenching stories of unnecessary suffering out there
Rational solutions
THANK [email protected]
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