COMPUTISTBIO-NANOTECH
DESIGNING THE RIGHT DRUG COMPOUND FOR THE RIGHT DISEASE TARGET
Live Webinar November 16 - 19, 2015Discovering Small Molecule Protein-Protein Interaction Inhibitors
through Computational Design
Watch the webinar http://www.computistresearch.com/webinar.html
© 2015 Computist Bio-Nanotech
COMPUTIST BIO-NANOTECHDesigning the right drug compound for the right disease target
Dr Wolfgang Kissel
Strategy and Business DevelopmentA/Prof. Herbert Treutlein
Co-Founder and CEO
• Expert in developing and
implementing strategies,
organizational excellence,
leadership.
• Expert in molecular
modelling and computational
drug design
Discovering Small Molecule Protein-Protein Interaction Inhibitors
through Computational Design
Presenters
© 2015 Computist Bio-Nanotech
Highlights of this WebinarDesigning the right drug compound for the right disease target
• A novel solution for a non-existing problem
• The everyday Challenge of R&D
• Trend reversals and game changers
• Defining Methods
• Small molecule Protein-Protein Interaction Inhibitors
• Ras/Raf example
• Benefits of computational design
• Q&A
© 2015 Computist Bio-Nanotech
Who benefits most from this WebinarDesigning the right drug compound for the right disease target
Who benefits most:
• R&D decision makers who want
to accelerate drug discovery
• R&D specialists who want to
get results quickly
• R&D Finance Managers on the
lookout for productivity gains
Tough
Decisions
Ahead
© 2015 Computist Bio-Nanotech
Key Insights from this Webinar IDesigning the right drug compound for the right disease target
Computational design, the future
way of drug discovery
• Small Molecule Protein-Protein-
Interaction inhibitors (smPPII) as a
new drug class → easy accessible
with computational methods
• Good computational methods are
validated and proven to work
PDB id: 3KUD
© 2015 Computist Bio-Nanotech
Key Insights from this Webinar IIDesigning the right drug compound for the right disease target
Computational methods, the future
way of smPPII discovery and design
• High speed and most cost-effective
smPPII development
• Find the needle in the haystacks –
not just another haystack
• Determination of drugability of
disease targets
• Double de-risk strategy in drug
development
➤ Quantum leap in R&D productivity
1010
107
© 2015 Computist Bio-Nanotech
Designing the right drug compound for the right disease target
A novel solution for a non-existing problem
© 2015 Computist Bio-Nanotech
Tropomyosin InhibitorDesigning the right drug compound for the right disease target
Our 2009 challenge
Novel fragment design method validated for protein-protein interaction
targets: Tropomyosin polymerization inhibitors (tested in vitro)
© 2015 Computist Bio-Nanotech
Tropomyosin InhibitorDesigning the right drug compound for the right disease target
Starting Point
• Tropomyosin not accepted as drug target
• Initial data showed specific isoforms in certain cancer cells (UNSW)
• Only cellular assay available to test SAR of inhibitors, no mode-of-action
• No clear way forward to establish tropomyosin as drug target
• Focus on non-muscle tropomyosin
© 2015 Computist Bio-Nanotech
Tropomyosin InhibitorDesigning the right drug compound for the right disease target
Process
4 rounds of design and optimization
• Speed: 1 month/round
• Our rigorous PM applied
© 2015 Computist Bio-Nanotech
Tropomyosin InhibitorDesigning the right drug compound for the right disease target
Outcome
• Design based on initial models as well as dynamical structures (MD simulations)
• Specificity: Access regions of sequence variability / remove of dynamin binding
• Establish SAR for compound series and mode-of-action
• Work was published and Tropomyosin accepted as drug target
• Novogen Ltd. acquired project and IP
© 2015 Computist Bio-Nanotech
Designing the right drug compound for the right disease target
The everyday Challenge of R&D
© 2015 Computist Bio-Nanotech
The Everyday Challenge for R&DHigh input, low output
Constant pressure:
• Too expensive, too slow, too risky
• Alleged productivity decline
• Small Molecule R&D unprofitable
• Ongoing fight for recognition
• Small vs. big molecules
© 2015 Computist Bio-Nanotech
Rising Costs for ever more expensive cures
Trend to biologic (protein-based) drugs
• Higher prices
• Higher profitability than Small Molecules
→ increasing health-care costs
OECD Data for Health
Expenditure: e.g. 17% of
GDP in the USA, 2010.
© 2015 Computist Bio-Nanotech
Finding Novel Molecules That Work
Novel Drug Compounds: The needle in the haystack
Q: How many possible drugs could be synthesized?
A: Synthesizable molecules: 1040 ≈ (number of stars)2
• Easy to handle: 1010
General Screening Libraries in HTS: 106
⇒ Unlikely that HTS or VS will find a drug/lead candidate in one single experiment
⇒ From diverse to highly focused libraries through iterative screening cycles
⇒ Computist delivers binding mode, mode of action, new compound options
Computational approach not restricted to compound libraries
1010
107
© 2015 Computist Bio-Nanotech
Designing the right drug compound for the right disease target
Trend reversals and game changers
© 2015 Computist Bio-Nanotech
Trend Reversals on the Horizon
Computational Design of drug compounds
Design molecules that interact with (this is
what we are doing):
• Surfaces
• Non-standard and standard binding sites
• Reliable binding mode and mode-of action
on protein surfaces
• Drugability evaluation
1010
© 2015 Computist Bio-Nanotech
Trend Reversals on the Horizon
Small Molecule Protein-Protein Interaction Inhibitors?
• Higher R&D productivity
• Higher profitability
→ lower prices possible
Small Molecule Protein-Protein Interaction Inhibitors!
• Higher success rate in later development stages
• Can replace biologic (protein-based) drugs
• Convenient application: oral delivery vs. injection
• More attractive than conventional small molecule R&D
© 2015 Computist Bio-Nanotech
Game Changers for Solutions Have ArrivedDesigning the right drug compound for the right disease target
Manifold acceleration of Discovery by Computational Design
• Compounds come with Mode-of-Action
• Optimizing good compounds to great compounds
• Up to 80% time savings
• Up to 80% cost savings
• “Impossible” projects now doable
© 2015 Computist Bio-Nanotech
Designing the right drug compound for the right disease target
Small Molecule Protein-Protein Interaction Inhibitors
© 2015 Computist Bio-Nanotech
Prospects of Small Molecule PPIIs
Emergence of a new class of Therapeutics
De-risking: shift of development risk to early stage• Double de-risking in combination with computational design
Simplification of disease targeting
• Convenient application: oral delivery vs. injection
© 2015 Computist Bio-Nanotech
Protein-Protein Interaction Inhibitors (PPII)Designing the right drug compound for the right disease target
Small Molecule Protein-Protein Interaction Inhibitors
• Targeting specific ‘hot spots’ on the protein surface, a growing trend
From: Meier, C., et al. (2013). Drug Discovery Today, 18(13-14), 607–609. Study by “The
Boston Consulting Group.”
© 2015 Computist Bio-Nanotech
Protein-Protein Interaction Inhibitors (PPII)Designing the right drug compound for the right disease target
Small Molecule Protein-Protein Interaction Inhibitors
• PPII development considered risky in early stage but
• Computational methods de-risk PPII development through:
• Our MFMD evaluates quickly drugability of target
• Fast, reliable low cost evaluation with virtual screening
• Tailor-made design of early stage compounds.
• More projects/targets evaluated and less money spent
© 2015 Computist Bio-Nanotech
Protein-Protein Interaction Inhibitors (PPII)Designing the right drug compound for the right disease target
Small Molecule Protein-Protein Interaction Inhibitors
Examples:
• Chemokine receptor interactions (e.g., Pfizer’s Selzentry),
• Integrin interactions (e.g., SAR code’s Lifitegrast),
• p53-MDM2 interaction (e.g., Roche’s RG7112).
Emerging market with highly attractive prospects
• 15 projects in development (2013)
• Licensing agreements crossed $1B (2012)
From: Meier, C., et al. (2013). Drug Discovery Today, 18(13-14), 607–609. Study by “The
Boston Consulting Group.”
© 2015 Computist Bio-Nanotech
Designing the right drug compound for the right disease target
Defining Methods
© 2015 Computist Bio-Nanotech
Computist’s Defining Methods: Designing the right drug compound for the right disease target
The heart of our method: Multiple Fragment Molecular Dynamics MFMD
Quantum Mechanics QM:
• Overcomes limitations of current force-field based methods (MM)
for small molecule ⟷ target interactions
Our Dynamical Score:
• Adds structural dynamical stability to find the right compound
© 2015 Computist Bio-Nanotech
Benefits of Computational Design Designing the right drug compound for the right disease target
Benefits of our MFMD approach:
• Explore and determine drugability of a target’s binding site
• Determine and map out binding site features using
your preferred small fragments
• MFMD enables precision docking of molecules
• Design optimized compounds with MFMD fragment
clusters combined with docked molecules
• Design specific compounds through mapping out
differences of MFMD clusters from two targets
© 2015 Computist Bio-Nanotech
Our Unique Skills and Methods AppliedDesigning the right drug compound for the right disease target
Computational Design of Protein-Protein Interaction Inhibitors
• Molecules designed to interact with surfaces / non-standard binding sites
• Proven success in our PPII design through experimental verification:
• Small molecules as tropomyosin polymerization inhibitors
• Novel fragments suitable for inhibitor design the Ras/Raf interaction
Small Molecule Alternatives for Protein Drugs
• Protein drugs are often used as PPIIs.
• Our technology proved successful in designing small molecules that
can replace an antibody
• All our designed PPIIs are small molecules or peptides
1010
© 2015 Computist Bio-Nanotech
Designing the right drug compound for the right disease target
Ras/Raf Example
© 2015 Computist Bio-Nanotech
Ras/Raf Protein-Protein Interaction InhibitorDesigning the right drug compound for the right disease target
Computational Design of Protein-Protein Interaction Inhibitors
• Proven success in our PPII design through experimental verification:
• Designed peptides to inhibit the Ras/Raf interaction in 1998
• Identified novel fragments suitable for inhibitor design the Ras/Raf
interaction in 2014 (collaboration with Circa Group Pty Ltd)
© 2015 Computist Bio-Nanotech
MFMD Scans
(selected fragments)
methyl-gua
Design of Ras/Raf interaction inhibitorsDesigning the right drug compound for the right disease target
© 2015 Computist Bio-Nanotech
MFMD Scans
(selected fragments)
Design of Ras/Raf interaction inhibitorsDesigning the right drug compound for the right disease target
phenol
© 2015 Computist Bio-Nanotech
MFMD Scans
(selected fragments)
Design of Ras/Raf interaction inhibitorsDesigning the right drug compound for the right disease target
benzene
© 2015 Computist Bio-Nanotech
2015: Fragment-based small molecule design
• Identified and verified fragments suitable for PPII
design leading to novel NCEs.
• Fragments are based on levoglucosenone.
• Experimentally verified
• IP is shared with Circa Group Pty. Ltd.
• Further discussions possible (NDA)
Design of Ras/Raf interaction inhibitorsDesigning the right drug compound for the right disease target
© 2015 Computist Bio-Nanotech
Designing the right drug compound for the right disease target
Benefits of Computational Design
© 2015 Computist Bio-Nanotech
😠Highly
expensive
No
Mode-of-action
Benefits of Computational DesignDesigning the right drug compound for the right disease target
• Quality of compounds
• Speed
• Cost per project
• Tailored compounds
• Mode-of-action clarified
• More projects/$$$ invested
↓
Increased success rate of projects
Experimental FragmentScreening
Computist’sMFMD
100-1000
fragments
Purchase
Fragments
Wet/NMR
Screening
Hits
50
Small
Fragments
MFMD
Tailored
Compound
Design
CompoundsFragment
Hits
Significantly
lower cost
Mode-of-action
clarified
😉
© 2015 Computist Bio-Nanotech
Summary and ConclusionDesigning the right drug compound for the right disease target
Combining Small Molecule PPII Discovery with Computational Design
• Access new class of drugs quicker, with
lower risk and at lower cost
→ higher R&D ROI
• From good PPII candidates To great PPIIs
• “Impossible” projects now doable
© 2015 Computist Bio-Nanotech
What We Do and How We Work Together Designing the right drug compound for the right disease target
Computational discovery & design of small molecule compounds• The most productive alternative to HTS
Our rigorous process leads to quicker
and better results
Our customized design cycles are clear-
cut and focused on your goals.
Together we change the way your drug candidates are discovered and developed
Computer Model:
Binding Mode & Specificity
Compound Data
(from client)
Wet Screening
performed by client
Compound Design
© 2015 Computist Bio-Nanotech
For Whom It Works BestDesigning the right drug compound for the right disease target
De-risking drug discovery
Existing infrastructure: Manifold optimization of drug discovery
No infrastructure: Jump start a drug discovery pipeline with
affordable infrastructure
Being stuck: Accelerating slow progressing/difficult projects
© 2015 Computist Bio-Nanotech
The Computist DifferenceDesigning the right drug compound for the right disease target
We are Digital Accelerators of Drug Discovery
Superior Value Creation
• Quick Mode-of-Action/binding mode clarification
• Better and improved compounds
• Earlier “time to market”
• Improved IP position
Significant Cost Savings
• Minimal infrastructure cost / investment
• Less personnel and material cost
• Accelerated process
Rigorous and disciplined project execution
+
+
© 2015 Computist Bio-Nanotech
“If you always do what you've always done, you'll always get
what you've always got!”
Henry Ford
© 2015 Computist Bio-Nanotech
Designing the right drug compound for the right disease target
Q&A
Computist Bio-Nanotech Pty Ltd
Scoresby, VIC, Australia
+61 412 367 935
www.computistresearch.com
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