We will discuss how we classified and calculated properties for over 21 million commercially available compounds using a variety of ChemAxon and in-house tools (and aggregated properties). We will show a summary of the analysis of the data and show how we will use that to build better virtual screens.

1. Building innovative
drug discovery alliances
Classification and analysis of 22 million
commercially available compounds
ChemAxon EUGM May 2013

2. PAGE
Agenda
 About Evotec
 About EVOsource
 Calculating Properties
 Analysis of the data
 Final Thoughts
1

3. PAGE 1) Manfred Eigen (*1927), German biophysical chemist and one of the worldwide leading pioneers in biotechnology. In 1967, he won the Nobel Prize in Chemistry for his
work on a special measuring method of fast chemical reactions, which, until then, were considered to be immeasurable. He initiated the foundation of Evotec AG.
A global company with a complete offering
Evotec worldwide operations
Sales representation (Boston, Tokyo)
Operations & sales representation
2
San Francisco,
US
~30 employees
 Compound
Procurement
 Compound QC
and storage
Abingdon,
UK
~215 employees
 Med Chem
 Comp Chem
 DMPK
 Structural biology
Munich,
Germany
~30 employees
 Phospho-
proteomics
 Chemical
proteomics
Göttingen, Germany
~50 employees
 Metabolics
 Regenerative
Medicine
Thane,
India
~130 employees
 Library synthesis &
mgmt.
 Development
chemistry
Hamburg,
Germany
~200 employees
 Screening
 HTS,NMR
 in vitro & in vivo
biology
Manfred Eigen1) Campus

4. PAGE
Agenda
 About Evotec
 About EVOsource
 Calculating Properties
 Analysis of the data
 Final thoughts
3

5. PAGE
EVOsource
4
Compound Sourcing
 Multiple search terms
 Single or combination
Category Count
 Suppliers 218
 Catalogues 539
 Unique
Compounds
22156696
 Parts 92490159

6. PAGE
EVOsource
5
Compound selection
 Can order from stores
 Can see if ordered
 Can order from supplier
 Can request a quote
 Can see if available in another
lab (or site)
 Additional information displayed
 JChem Cartridge accessed
through Java Persistence API
 Marvin Applet
 Structure to Name
 Standardizer

7. PAGE
The challenges of loading supplier catalogues
Integrated Cyclic Process
Process
Contact
Receive
Prepare
Load
 Receive catalogues
– New catalogues
– Catalogue updates
 Prepare catalogues
– Convert to SD file
– Structure Checker
– Structure to Name
– Name to Structure
 Contact Suppliers
– Existing suppliers
– Preferred suppliers
– New suppliers
 Process
– Fix errors
– Expire old data
 Load catalogue data
– Multiple parallel
processes
6

8. PAGE
Agenda
 About Evotec
 About EVOsource
 Calculating Properties
 Analysis of the data
 Final Thoughts
7

9. PAGE
Drug likeness categories
Classification of compounds
Feature count is defined as: # of 5- and 6-membered aromatic rings + # of Lipinski acceptors + # of Lipinski donors
Drug like
No SS fails
Lipinski fails ≤ 1
Additional property
constraints:
MOE LogP ≤ 6
MW ≤ 600
Rot bonds ≤ 10
EVO LogS ≥ -7
TPSA ≤ 180
Amber
No red SS fails
Lipinski fails ≤ 1
or
No SS fails
Lipinski fails ≤ 2
Red
Everything else!
Lead like
No SS fails
No Lipinski fails
Additional property
constraints:
MOE LogP ≤ 3.5
MW ≤ 350
Rot bonds ≤ 6
EVO LogS ≥ -5
TPSA ≤ 140
Fragments
No SS fails
No FSS fails
Lip. donors 1-3
Lip. acc. 0-4
MOE LogP ≤ 3.0
MW 150-350
Rot bonds ≤ 5
EVO LogS ≥ -3
TPSA ≤ 70
Feature count 4-7
8

10. PAGE
Property calculations
Historical process
Historical process
Export all structures
calculate properties using MOE
Structural alerts using MOE
Stored in a MOE database
Problems
Only available to Comp Chem Group
Difficult to update and time consuming
Different values using different tools – chemists use ChemAxon tools
to calculate properties
9

11. PAGE
Property calculations
New process stage 1
 Calculate simple properties
 Use ChemAxon JChem cartridge calculations where available
 Weekly job that calculates properties for new structures
 LogS uses MOE to calculate
 LogS manually updated every 2 months
10

12. PAGE
Calculated Results
Breakdown of chemical space by simple descriptors
MW HBD
HBA
logP RotB
11

13. PAGE
MOE SMARTS converted to ChemAxon format
Structural alerts using two types of filter
 121 SMARTS Structural Alerts – general screening compounds
 19 SMARTS Fragment filters – fragment screening
Assign compounds to category – fragment, lead like
etc.
Problems
 Took 6 months to calculate substructure search as had to be broken into
small chunks
 MOE SMARTS not automatically converted to ChemAxon format
Property calculations
New process stage 2
12

14. PAGE
Quantitative Estimate of Drug-likeness (QED)
New process stage 3
Quantifying the chemical beauty of drugs, A. L. Hopkins et al, Nature Chemistry 2012, 4, 90–9813
 QED calculation is based on similar parameters used to assign compounds to the Evotec
categories, each parameter is weighted from a model fitting
 A proof of concept was carried out on a subset of our screening collection
 Literature weights were modified with a bias in favour of structural alerts
 LogD was substituted for ALogP to consider ionisation
 QED calculation runs as a weekly job
Weighted QED
Relativefrequency
0.49 0.67

15. PAGE
What is a beautiful molecule?
Evotec weighted QED
14
QED = medium
QED = high
QED = low

16. PAGE
Agenda
 About Evotec
 About EVOsource
 Calculating Properties
 Analysis of the data
 Final Thoughts
15

17. PAGE
EVOsource composition
16
EVOsource composition
for Evotec drug-likeness classes
Weighted QED
Relativefrequency
15.3%
2.9M
26.9%
5.3M
57.8%
11.1M
0.49 0.67
EVOsource composition
for QED index
Lead-like 3.1M
Fragment-like 1M
Red 2.1M
Amber 4.2M
Drug-like 8.1M

18. PAGE
Excellent agreement of QED and Evotec flags to
discriminate between different drug-like classes
17
0.670.49
Relativefrequency
Weighted QED
QED index profile of each Evotec drug-likeness class

19. PAGE
EVOsource QED distribution shows large
overlap with orally available drugs
18
0.670.49
Weighted QED
Relativefrequency
Orally available
(682 analyzed out of 770)
EVOsource
Orally available drugs
EVOSource

20. PAGE
Agenda
 About Evotec
 About EVOsource
 Calculating Properties
 Analysis of the data
 Final Thoughts
19

21. PAGE
Final thoughts and Acknowledgements
 EVOsource provides:
 A useful tool for our chemists in ordering compounds for our clients
 A tool for our Computational Chemists to do analyses of chemical space to better support our clients in
library design
 QED calculation is providing a useful tool for filtering data to quickly make virtual
libraries
 QED has been added to latest version of ChEMBL
20
Thanks to:
Dr Oliver Barker
Dr Mirco Meniconi
Catherine Reisser
Dr Dan Warner

22. Your contact:
Building innovative
drug discovery alliances
Ian Berry Bob Marmon
Manager, Informatics Senior Applications Developer
+44.(0).1235.441451 Office +44.(0).1235.441402 Office
+44.(0) 7802.438044 Mobile +44.(0).1235.861561 Switchboard
+44.(0).1235.441503 Fax +44.(0).1235.441503 Fax
ian.berry@evotec.com bob.marmon@evotec.com