Fernando Huerta (RISE Bioscience & Materials, SE) Alexander Minidis (Collaborative Drug Discovery - CDD VAULT, Sweden) How much information does the scientists need to design new potential drugs? A thorough overview of public scientific information sources (open access) and methods to collect, process, analyse and visualize this information will be presented. A direct application of such free available information in conjunction with freeware will be described in relation with the efforts of the scientific community to find effective medicines for the ZIKA virus.

1. Research Institutes of Sweden
FREEWARE & OPEN
ACCESS DATABASES
Fernando F Huerta
Process and Pharmaceutical Development
Division Bioscience and Materials
High T&P
Towards a Wiki Drug Discovery?

2. Research Institutes of Sweden
Process and Pharmaceutical Development
Division Bioscience and Materials
High T&P

3. Research Institutes of Sweden
FREEWARE & OPEN
ACCESS DATABASES
Fernando F Huerta
Process and Pharmaceutical Development
Division Bioscience and Materials
High T&P
Towards a Wiki Drug Discovery?

4. Is it possible to use “free” accesible information
to run a drug design project?
BACKGROUND

5. WHAT DO WE NEED?
1.What
2.Where
3.How
4.Example
5.Reference

6. WHAT DO WE NEED?
1.Drug Design
2.Where
3.How
4.Example
5.Reference

7. WHAT DO WE NEED?
1.Drug Design
2.Information
3.How
4.Example
5.Reference

8. WHAT DO WE NEED?
1.Drug Design
2.Information
3.Mining
4.Example
5.Reference

9. WHAT DO WE NEED?
1.Drug Design
2.Information
3.Mining
4.Zika
5.Reference

10. WHAT DO WE NEED?
1.Drug Design
2.Information
3.Mining
4.Zika
5.Reference
FREE VS COMMERCIAL

11. Commercial SystemsFree / Open Source Systems
FREE vs COMMERCIAL

12. WHAT DO WE NEED?
1.What
2.Where
3.How
4.Example
5.Reference

13. The Big Picture
DRUG DISCOVERY & MOLECULAR PROPERTIES

14. DRUG DISCOVERY & MOLECULAR PROPERTIES

15. DRUG DISCOVERY & MOLECULAR PROPERTIES
ENTER SYSTEMIC CIRCULATION
(ABSORPTION)

16. DRUG DISCOVERY & MOLECULAR PROPERTIES
TISSUE/ORGAN DISTRIBUTION

17. DRUG DISCOVERY & MOLECULAR PROPERTIES
CELLULAR PERMEABILITY

18. DRUG DISCOVERY & MOLECULAR PROPERTIES
BIND TO RECEPTOR

19. DRUG DISCOVERY & MOLECULAR PROPERTIES
ELIMINATION

20. DRUG DISCOVERY & MOLECULAR PROPERTIES
Pharmaco-kinetics &
Pharmaco-dynamics
ENTER SYSTEMIC CIRCULATION
(ABSORPTION)
TISSUE/ORGAN DISTRIBUTION
CELLULAR PERMEABILITY
BIND TO RECEPTOR
ELIMINATION
BIOLOGICAL PROPERTIES
(measured)
STRUCTURAL PROPERTIES
PHYSICO CHEMICAL PROPERTIES
(calculated)
Chemical & Biological
properties

21. DRUG DISCOVERY & MOLECULAR PROPERTIES
Pharmaco-kinetics &
Pharmaco-dynamics
ENTER SYSTEMIC CIRCULATION
(ABSORPTION)
TISSUE/ORGAN DISTRIBUTION
CELLULAR PERMEABILITY
BIND TO RECEPTOR
ELIMINATION
BIOLOGICAL PROPERTIES
(measured)
STRUCTURAL PROPERTIES
PHYSICO CHEMICAL PROPERTIES
(calculated)
Chemical & Biological
properties
CORRELATIONS

22. Chemical & Biological properties Data Mining
Available information (building correlations)
New Potential
Candidate Drug
DRUG DISCOVERY & MOLECULAR PROPERTIES CORRELATIONS
Structural
Solubility
logP / logD
pKa
PSA
Docking exp*
Lipinski
Calculated Experimental
Potency
Selectivity
caco2
Metabolism
herg

23. one more thing…

24. one more thing…
Nature
HTS
Analogy
Chemical Evolution
Structures and associated data

25. WHAT DO WE NEED?
1.What
2.Where
3.How
4.Example
5.Reference

26. 1.What
2.Where
3.How
4.Example
5.Reference
WHERE TO FIND THE INFORMATION
Information Sources (open access)
- easy integration with analytical platforms (free and commercial)
- most popular (and up to date)
… and many more

27. 1.What
2.Where
3.How
4.Example
5.Reference
WHERE TO FIND THE INFORMATION
▪ Free
▪ NCBI
▪ FTP / API
▪ BioAssay / Compounds

28. 1.What
2.Where
3.How
4.Example
5.Reference
WHAT DO WE NEED?

29. 1.What
2.Where
3.How
4.Example
5.Reference
WHAT DO WE NEED?
Data Mining & Visualization (open access)
www.predictiveanalyticstoday.com

30. 1.What
2.Where
3.How
4.Example
5.Reference
WHAT DO WE NEED?
Data Mining & Visualization (open access)
▪ Popular
▪ User community
▪ Integration
▪ Compounds & reactions
▪ Flexible (applications)

31. 1.What
2.Where
3.How
4.Example
5.Reference
WHAT DO WE NEED?
… we do not have own data to compare with…

32. 1.What
2.Where
3.How
4.Example
5.Reference
WHAT DO WE NEED?
… drugs for the same target look alike…
Norfloxacin
(Noroxin™)
Ciprofloxacin
(Cipro™)
Sparfloxacin
(Zagam™)
Grepafloxacin
(Raxar™)
Nexium® Rabeprazole® Pantoprazole®
Seroquel®Loxapine®
Drug Discovery Today 2011, 16, 722
Drug Discovery Today 2011, 16, 779

33. 1.What
2.Where
3.How
4.Example
5.Reference
WHAT DO WE NEED?
… we do not have own data to compare with…
STRUCTURAL ANALYSIS
+ ASSOCIATED DATA

34. 1.What
2.Where
3.How
4.Example
5.Reference
WHAT DO WE NEED?

35. WHAT DO WE NEED?
1.What
2.Where
3.How
4.Example
5.Reference
www.healthmap.org
Spread by the bite of Aedes species mosquito
Harmless symptoms
Transferred to fetus (birth defects)
1947 and 2016
No vaccine / medicine
ZIKA VIRUS

36. ZIKA: OPEN ACCESS DRUG DISCOVERY PROJECT
www.openzika.ufg.br
http://bioinfo.imtech.res.in/manojk/zikavr/index.php
Collection of biological & chemical data
464 potential drug targets
Direct mining possible (not straightforward)
Download data for external mining
www.nature.com/scientificreports (DOI: 10.1038/srep32713)
ZIKA
Genome
Known
Viruses
Genome
Comparison
Potential
Candidate
Drugs
FDA approved
ready for clinical
trials

37. ZIKA: OPEN ACCESS DRUG DISCOVERY PROJECT
DB01693
DB01752 DB03996
DB04331
DB07064 DB08032 DB08033 DB08037
DB08198
DB08239 DB08244 DB08246 DB08250 DB04473
http://bioinfo.imtech.res.in/manojk/zikavr/index.php
3 main biological targets:
Interleukin-4-receptor
subunit alpha
Genome polyprotein
Kinesin-like protein KIF11
1 structural “coincidence”
6 Molecules share the
same subgraph

38. ZIKA: OPEN ACCESS DRUG DISCOVERY PROJECT
Nature Medicine, vol 22, 10, 2016, 1101 (doi:10.1038/nm.4184 )
Emricasan PHA-690509 Niclosamide
pan-caspase inhibitor
neuroprotective
activity
not suppress ZIKV
replication
cyclic-dependent kinase
inhibitor (CDKi)*
antiviral activity
FDA-approved drug
treatment of worm
infections
*Ten structurally unrelated CDKis inhibit ZIKA replication

39. ZIKA: OPEN ACCESS DRUG DISCOVERY PROJECT
Taken together …
1 structural “coincidence”
▪ Interleukin-4-receptor subunit alpha
▪ Genome polyprotein
▪ Kinesin-like protein KIF11
cyclic-dependent kinase inhibitor (CDKi)
Nature Medicine 22, 10, 2016, 1101http://bioinfo.imtech.res.in/manojk/zikavr/index.php
Ten structurally unrelated CDKis inhibit ZIKA replication
1. Search bioactives related to the subgraph
2. Search for KIF11 inhibitors (Structural comparison)
3. Search for CDK inhibitors (Structural comparison)
subgraph
http://www.pharmakarma.org/

40. ZIKA: OPEN ACCESS DRUG DISCOVERY PROJECT
CDKi’s (27 molecules)
Nature Medicine 22, 10, 2016, 1101
13/27
11/27
4/27
Ten structurally unrelated CDKis inhibit ZIKA replication
257 structurally unrelated CDKi’s
(based on subgraph)
…structures and bio-assay data available
1452 CDKi’s found (CDK1-CDK20)
http://www.pharmakarma.org/

41. ZIKA: OPEN ACCESS DRUG DISCOVERY PROJECT
14 Molecules in www.drugbank.ca
1 structural “coincidence”
▪ Interleukin-4-receptor subunit alpha
▪ Genome polyprotein
▪ Kinesin-like protein KIF11
http://bioinfo.imtech.res.in/manojk/zikavr/
index.php
subgraph
http://www.pharmakarma.org/
7/14
6/14 0/5776
KIF11 inhibitors found:
Graph analogues found: 1100
▪ 18 reported as Kinesin like protein 1
▪ Kinesin superfamily (non-standard names)
▪ >1000 compounds (Tanimoto >0.7)

42. ZIKA: OPEN ACCESS DRUG DISCOVERY PROJECT
Nature Medicine 22, 10, 2016, 1101
http://bioinfo.imtech.res.in/manojk/zikavr/index.php
Match Pairs
SAR
Lipinski
R-Group Decomposition
Pharmacophore
Summary
▪ Analogues with same subgraph (Tanimoto >0.7)
▪ Non related structures active on same targets
▪ Bioassay data
▪ Other analysis possible

43. 1.What
2.Where
3.How
4.Example
5.Reference
WHAT DO WE NEED?

44. 1.What
2.Where
3.How
4.Example
5.Reference
WHAT DO WE NEED?
REAXYS API

45. 1.What
2.Where
3.How
4.Example
5.Reference
WHAT DO WE NEED?
REAXYS API
▪ CDKi’s ca 40000 structures (25x more)
▪ KIF11 inhibitors ca 4000 structures
(1000 less)
▪ Equal amount of data
▪ Same conclusions

46. OUR ANSWERS
Quality
Accessibility
Up to Date
but …
Is it possible to use “free” accesible information
to run a drug design project?
YES

47. OUR ANSWERS
Towards a Wiki Drug Discovery?
NO
All others
Unmet medical needs
Orphan diseases
YES
Neglected diseases (Malaria)

48. FREE vs COMMERCIAL
Commercial SystemsFree / Open Source Systems
YOUR TASTE!
YOUR NEEDS!

49. ICIC Heidelberg, October 23-24, 2017
• CHEMNOTIA
• REAXYS
• PUBCHEM
• KNIME (& Contributors)
• Alexander Minidis, PhD
Collaborative Drug Discovery
www.pharmakarma.org/blog
ACKNOWLEDGEMTS
Research Institutes of Sweden
Process and Pharmaceutical Development
Division Bioscience and Materials
THANK YOU!