Webinar: Discovering Small Molecule Protein-Protein Interaction Inhibitors through Computational Drug Design

COMPUTIST
BIO-NANOTECH
DESIGNING THE RIGHT DRUG COMPOUND FOR THE RIGHT DISEASE TARGET
Live Webinar November 16 - 19, 2015
Discovering Small Molecule Protein-Protein Interaction Inhibitors
through Computational Design
Watch the webinar http://www.computistresearch.com/webinar.html

© 2015 Computist Bio-Nanotech
COMPUTIST BIO-NANOTECH
Designing the right drug compound for the right disease target
Dr Wolfgang Kissel
Strategy and Business Development
A/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

Highlights of this Webinar
• 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

Who benefits most from this Webinar
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

Key Insights from this Webinar I
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

Key Insights from this Webinar II
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

A novel solution for a non-existing problem

Tropomyosin Inhibitor
Our 2009 challenge
Novel fragment design method validated for protein-protein interaction
targets: Tropomyosin polymerization inhibitors (tested in vitro)

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

Process
4 rounds of design and optimization
• Speed: 1 month/round
• Our rigorous PM applied

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

The everyday Challenge of R&D

The Everyday Challenge for R&D
High 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

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.

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

Trend reversals and game changers

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

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

Game Changers for Solutions Have Arrived
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

Small Molecule Protein-Protein Interaction Inhibitors

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

Protein-Protein Interaction Inhibitors (PPII)
• 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.”

• 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

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.”

Defining Methods

Computist’s Defining Methods:
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

Benefits of Computational Design
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

Our Unique Skills and Methods Applied
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

Ras/Raf Example

Ras/Raf Protein-Protein Interaction Inhibitor
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)

MFMD Scans
(selected fragments)
methyl-gua
Design of Ras/Raf interaction inhibitors

MFMD Scans
phenol

MFMD Scans
benzene

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)

😠
Highly
expensive
No
Mode-of-action
• Quality of compounds
• Speed
• Cost per project
• Tailored compounds
• Mode-of-action clarified
• More projects/$$$ invested
↓
Increased success rate of projects
Experimental
Fragment
Screening
Computist’s
MFMD
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
😉

Summary and Conclusion
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

What We Do and How We Work Together
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

For Whom It Works Best
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

The Computist Difference
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
+
+

“If you always do what you've always done, you'll always get
what you've always got!”
Henry Ford

Q&A
Computist Bio-Nanotech Pty Ltd
Scoresby, VIC, Australia
info@computistresearch.com
+61 412 367 935
www.computistresearch.com

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