To learn more and watch the webinar, go to: https://insidescientific.com/webinar/optimize-the-value-of-your-research-investment-outsourcing-molecule-design/ Finding, designing, and optimizing new molecules can be easier, faster, and less expensive with computational chemistry. By predicting the physicochemical properties and biological activities of compounds prior to synthesis, you avoid unnecessary wet chemistry and save time and money. In this webinar, Dr. Martin Slater discusses common challenges in medicinal chemistry, molecule design, and drug discovery that can be overcome with computational methods. He presents examples of how his team of expert modelers has worked with researchers in the pharmaceutical, agrochemical, and flavor & fragrance industries, including using a ligand-centric approach to discover a novel therapy for urinary tract infections, testing in silico hypotheses in vitro, a 3D clustering method to deliver diverse fragment libraries, and discovering and patenting a novel seed treatment. Key Topics Include: - Recognize new opportunities to use computational chemistry in your research - Understand how molecular modeling expertise can provide intelligent and innovative solutions for your projects, without having to recruit in-house - How computational methods can help to prioritize molecules most likely to succeed and avoid unnecessary wet chemistry - How Cresset Discovery can help with strategic contributions, written proposals, flexible service packages, and project monitoring and reporting

1. Welcome!
Optimize the Value of Your
Research Investment:
Outsourcing Molecule Design
Director
Cresset Discovery
Martin Slater, PhD

2. Optimize the Value of your Research Investment:
Outsourcing Molecule Design
Dr Martin Slater

3. © Cresset
www.cresset-group.com/discovery
> Value of computational chemistry in drug discovery
> Challenges of molecular discovery
> Navigating through roadblocks to project success
Overview
> Advantage of outsourcing molecular modeling
> Access to expert modeling
> Case examples
> How outsourcing has delivered value
> Working with Cresset Discovery

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Challenges in drug discovery
It’s complicated!
Multidisciplinary, multiparameter
problem
Main challenge
Understanding enough about the
biological system and data to
solve the problem with chemistry

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> IP space is becoming more crowded
> Regulatory requirements more stringent
> Companies are attempting to reduce risk
and overheads in every way possible
> Critical need for companies to efficiently
convert their increasingly diverse list of
biological targets into viable and
developable drug development programs
Challenges for drug discovery organizations
Hit
discovery
Hit to
lead
Lead
optimization
Candidate
selection
Target ID and
validation
Classical medicinal chemistry ‘linear path’

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Why do computational chemistry?
> Deploying computational
chemistry can maximize
ROI on R&D spend
> Will apply novel means of
molecular hit discovery
and molecular design
> Allow efficiency gains
> Enhance design effort and
promote more gainful use of
chemistry FTE’s
> Provide more sensible input
for biological testing
How modeling can ‘enable’ modern medicinal chemistry

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Why outsource?

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Molecule design roadblocks if you have an in-house team
Already working
to capacity
Other projects not
being progressed
Complex projects
taking too long
Output is slow
and expensive
Buy and maintain IT
infrastructure

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Molecule design roadblocks if you don’t have an in-house team
Output is slow
and expensive
Lots of wet chemistry
projects are slow and
expensive to progress
CRO relationship
not effective
No budget for full-
time modelers

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As your CRO we remove obstacles and roadblocks
Optimize value
of research
investment
Accelerate
creation of
commercial
assets
Discover fresh ideas
that contribute to the
strategic direction of
your research
Prioritize the molecules that
are most likely to succeed
Gain molecular
modeling expertise
without increasing FTEs
Avoid unnecessary
wet chemistry

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Challenges
Synthesis and designs - What to make? What NOT to make?
Avoid unnecessary (expensive) wet chemistry
Shortage of good computational chemists
In silico advantage
HTS plus med chem = $1m over 18 months
In silico plus med chem = $150k over 6 months
ROI for in silico discovery consultancy

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Dedicated team of expert modelers
Deployment of in silico methods that work for you
Access to powerful science, modeling software and infrastructure
Resource on demand
Collaborative working with seamless communication
Benefits of outsourcing to an in silico modeling team

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Expert molecular modeling advantage

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Cresset Discovery is a specialist molecular modeling CRO
Target
identification
• Target
discovery
• Target
deconvolution
Lead generation
and optimization
• Virtual screening
• QSAR
• De novo design
Preclinical
development
• Physicochemical
properties
• ADME-toxicity

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XED force field enables you to
> Gain detailed electrostatic description
of ligands and proteins
> Understand how structural changes
influence your electrostatics
> See how substituents influence the
electrostatics of cores and vice versa
Innovative science in Cresset software for results you can trust
Using off-atom charges, combined with
the redistribution of partial charges using
a Hückel method, enables the detailed
modeling of molecular electrostatics,
including lone pair directionality
The electrostatics of the binding site
show high complementarity to the ligand
and enable the prioritization of new
designs

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As your scientific partner we share your goals and challenges

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Broad range of targets and
therapeutic areas
g l o b a l r e a c h
• Enzymes
• Channels
• Receptors
• Transcription factors
• Anti-infectives
Cross-industry experience
Cross industry experience and expertise

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Expert team of in silico modelers
> Proven track record in delivering
drug discovery projects
> Dedicated team of experienced
molecular modelers provide
intelligent input and interpret results
> 300+ projects completed
Biology
Medicinal
chemistry
Medicinal
chemists
Director of
Consulting
Application
scientists
Computational
chemists
Account
manager
Project
manager
Computational
chemistry

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Case examples

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Requirement
Discovery of active molecules targeting a novel bacterial enzyme.
Cresset Discovery role
Combined cutting edge research with in silico drug discovery
expertise to successfully identify a set of novel inhibitors. In a proof
of concept, confirmed their ability to reduce pathogenicity in clinical
strains of uropathogenic E. coli.
Outcome
The current focus is in optimizing these hits and completing pre-
clinical development to be able to move further into clinical trials.
Ligand-centric approach to discover novel therapy for UTIs

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Biological Sciences - Microbiology:
Jason D. Oliver, Graham E. M. Sibley, Nicola Beckmann, Katharine S.
Dobb, Martin J. Slater, Laura McEntee, Saskia du Pré, Joanne
Livermore, Michael J. Bromley, Nathan P. Wiederhold, William W.
Hope, Anthony J. Kennedy, Derek Law, and Mike Birch
F901318 represents a novel class of antifungal drug that inhibits
dihydroorotate dehydrogenase
PNAS 2016 113 (45) 12809-12814; published ahead of print October 25,
2016, doi:10.1073/pnas.1608304113
Testing in silico hypotheses in vitro

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Innovative 3D clustering method delivers diverse fragment libraries
Requirement
Help US biotech build the maximum possible 3D diversity into small
libraries of fragments from a starting pool of over a million compounds.
Cresset Discovery role
Developed innovative clustering method that made it possible to
assess the 3D similarity across their virtual database of over 1.5
million fragments.
Existing techniques would have required an unfeasible amount of
computing power so we developed an entirely novel rapid clustering
method especially for the project. Our expertise in distributing
calculations to the cloud meant that we delivered the results that the
client needed on time and within budget.
Outcome
3D fragment library containing a significant number of compounds with
novel core structures that are viable targets for fragment generation.

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Secured series and follow-on funding
Requirement
Reduce project spend and help meet research goals.
Cresset Discovery role
Our expert modelers worked on a three-way collaboration with an
academic group and chemistry provider on a grant funded project.
The project enjoyed rapid progression, from inception to a novel and
selective series, with many of the problems associated with the target
ultimately solved.
Outcome
One potent series was well established and a second series had
potential to be explored. Follow-on funding secured.

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Tioxazafen: A New Broad-Spectrum Seed Treatment
Nematicide
Urszula Slomczynska, Michael S. South, Greg J. Bunkers, Donald
Edgecomb, Dawn Wyse-Pester, Shaun Selness, Yiwei Ding,
Jessica Christiansen, Kent Ediger, William Miller, Pana
Charumilind, Gregory Hartmann, Jeremy Williams, Matthew
Dimmic, Barry Shortt, William Haakenson, Al Wideman, Michael
Crawford, Michelle Hresko, and James McCarter
Discovery and Synthesis of Crop Protection Products. January 1,
2015 , 129-147
DOI:10.1021/bk-2015-1204.ch010
Novel seed treatment discovered and patented
Requirement
Help agrochemical company meet research goals by finding novel
small molecule nematicides to develop a new treatment to prevent
crop damage by nematodes.
Cresset Discovery role
Scientists from both parties worked closely throughout the project with
a combination of personal visits and regular conference calls.
Cresset consultants were an integral part of the discovery team, from
hit identification through lead optimization and the filing of patents.
Outcome
Multiple patents filed. New seed treatment launched to market.

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Working with Cresset Discovery

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> Gain access to an expert team not just
expensive individuals
> Strategic research direction
> Diverse team – flexibility, direction change
> Speed – rapidly engaged and quick start-up
> Global footprint
> Focused on the task
> Bespoke software capability
Customers tell us they have benefited from working with us
flexibility
bespoke
focus
speed
expertise

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Collaborative working
Project outsourced
Expert CADD scientists
work on customer project
Secure viewing
in real-time

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Testimonials
Cresset has consistently delivered insightful support to
our drug discovery efforts. In our experience, their
knowledge, responsiveness and collaborative approach
have set them apart from their competitors.
This is a very important and exciting project for my team
so thank you for your good work. The incredibly high hit
rate from your compound list [Blaze] is intriguing.
Cresset is a valuable partner in our drug discovery
programs. Their deep knowledge of computational
chemistry and its application to drug discovery is
enabling us to progress multiple projects across a wide
range of target classes very quickly and cost-effectively.
F2G have used Cresset Discovery for over two years. We really like the
powerful combination of excellent software tools and molecular design
expertise which we get from working with Cresset.
Dr Graham Sibley, Head of Chemistry, F2G
Cresset Discovery’s computational experience and high
standard of scientific support is ideally suited to help drive
the next stage of this project.
Dr Richard Boyce, Senior Director of Research, PhoreMost

29. © Cresset
www.cresset-group.com/discovery
As your CRO we remove obstacles and roadblocks
Optimize value
of research
investment
Accelerate
creation of
your
commercial
assets
Discover fresh ideas
that contribute to the
strategic direction of
your research
Prioritize the molecules
that are most likely to
succeed
Gain molecular
modeling expertise
without increasing
FTEs
Avoid unnecessary
wet chemistry

30. © Cresset
www.cresset-group.com/discovery
Proven track record of delivering comp chem solutions
> Founded 2002
> Software
> 15 of top 20 pharmaceutical companies
use Cresset technology in their research
programs
> Hundreds of customers in North America,
Europe, India, China, Japan, Korea
> Contract research
> 300+ projects delivered globally
> Support medicinal and computational
chemistry through ligand-based and
structure-based software and services
> Successful growth business
> 70+ staff across 3 continents

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