Molecular scaffolds talk, from ACS National Meeting in Indianapolis, IN, Sept. 8, 2013.

1. Molecular scaffolds are special
and useful guides for discovery
Jeremy Yang, UNM & IU
Cristian Bologa, UNM
David Wild, IU
Tudor Oprea, UNM
ACS National Meeting - Sept. 8-12, 2013 - Indianapolis, IN
CINF Graduate Student Research Symposium in Cheminformatics, Information Science, and Library Science

2. Molecular scaffolds are special
and useful guides for discovery
Jeremy Yang, UNM & IU
Cristian Bologa, UNM
David Wild, IU
Tudor Oprea, UNM
ACS National Meeting - Sept. 8-12, 2013 - Indianapolis, IN
CINF Graduate Student Research Symposium in Cheminformatics, Information Science, and Library Science

3. What is a molecular scaffold?
• "Ring-system"
• "Ring"
• "Core"
• "Framework"
Can you identify this famous scaffold?

4. Some famous scaffolds
beta – lactam
(penicillins,
cephalosporins )
Millions saved,
billions earned
steroid
(testosterone,
hydrocortisone, etc. )
Wonder drugs and
hormones
benzodiazepine
(Valium, flurazepam,
etc. )
“Mother’s little
helper”

5. Scaffolds are special because:
3D shape
Estradiol
docked into
ER-α
(OpenEye
Fred, Vida)

6. Scaffold scholarship & software
• Bemis & Murcko, “Molecular
frameworks”, 1996.
• Lewell et al., “Drug rings
database”, 2003.
• Wilkens et al., “HierS: hierarchical
scaffolds”, 2005.
• Ertl et al., “Quest for the Rings”,
2006.

7. • Clustering, indexing databases.
• Navigation of chemical space.
• Data reduction, visualization.
• R-group / SAR analyses.
• Bioactivity prediction.
• Promiscuity prediction.
Scaffold Applications
What can be done with scaffolds?
"The only rules that really matter are these: what a man can do and what a man can't do."
- Jack Sparrow

8. Scaffold Applications: Scaffold Hunter
Interactive exploration of chemical space with Scaffold Hunter,
S Wetzel, K Klein, S Renner, D Rauh, T Oprea, P Mutzel, H
Waldmann, Nat Chem Bio, 5, 2009, 581-583.

9. Scaffold Applications: Scaffold Hopper
Scaffold Hopper, NCATS/NCGC, http://tripod.nih.gov,
http://tripod.nih.gov/files/ACS_apr8_2013.pdf.

10. Scaffold Applications: CARLSBAD
CARLSBAD:
The Power to Explore Biological
Networks via Chemical Patterns
The CARLSBAD Database: A Confederated Database of Chemical Bioactivities,
S. L. Mathias, J. Hines-Kay, J. J. Yang, G. Zahoransky-Kohalmi, C. G. Bologa, O.
Ursu and T. I. Oprea, Database, 2013, bat044. http://carlsbad.health.unm.edu

11. Scaffold Applications: Molecule Cloud
The Molecule Cloud - compact visualization of large collections of
molecules, P Ertl and B Rohde, J. Cheminfo, 2012, 4:12.

12. Scaffold Applications: Badapple
(BioActivity Data Associative Promiscuity Pattern Learning Engine)
Translational Informatics Public Webapps:
http://pasilla.health.unm.edu/

13. See also my Badapple talk in CINF session "Integrative Chemogenomics Knowledge Mining Using NIH
Open Access Resources", Tues. Sept. 9, 10:45am, Rm. 140.
Scaffold Applications:
Badapple Promiscuity Plugin
Badapple Promiscuity
Plugin for BARD,
http://bard.nih.gov

14. Scaffold software: UNM-Biocomp-HScaf
(Open-source Google Code project)
http://code.google.com/p/unm-biocomp-hscaf/

15. UNM Translational Informatics Public Web Apps:
http://pasilla.health.unm.edu/
Demo web app: HScaf

16. Scaffold analysis algorithm
• Remove non-linking chains
• Keep linking chains
• Keep atoms multiply-bonded to rings and chains
• Special case: ignore solo-benzene.

17. HierS scaffold hierarchy
quinine
Bemis-Murcko
framework
scaffolds

18. Cheminformatics and scaffolds:
Relevant methods
• SSSR (Smallest Set of Smallest Rings)
• Canonicalization (e.g. Morgan, CanSMILES)
• Scaffolds vs. MCS (max common subgraph)
• Fingerprints, descriptors, similarity
• Proposed new method: scaffold-based similarity

19. More scaffold charms
• Patents, Markush, $$$.
• Lead discovery ~ scaffold discovery.
• Organic chemists like scaffolds.
• Scaffolds can be "privileged".

20. Scaffolds & drug-scaffolds, the privileged few
explaining a lot of activity...
Dataset:
BARD,
MLSMR,
MLP HTS
Totals: compounds:
373,802 ; scaffolds:
146,024 ; assays: 528
; wells/results:
30,612,714;
drugs: 283;
drugscafs: 1958
% total
activity
# scaffolds %
scaffolds
All 50% 1979 1.4%
All 75% 11,645 8%
Drugs 50% 54 2.8%
Drugs 90% 327 16.7%
“activity of DB” ~ # active scaffold-instances

21. Privileged scaffolds concept
Nature favors a few privileged scaffolds, a.k.a.
"privileged structures", for multiple receptors.
"What is clear is that certain “privileged structures” are capable
of providing useful ligands for more than one receptor and that
judicious modification of such structures could be a viable
alternative in the search for new receptor agonists and
antagonists."*
*Methods for drug discovery: development of potent, selective, orally effective
cholecystokinin antagonists, Evans et al., J. Med. Chem., 1988, 31, 2235.

22. News: antibiotic, scaffold:
Anthracimycin
Anthracimycin, a Potent Anthrax Antibiotic from a Marine-Derived Actinomycete,
Kyoung Hwa Jang et al., Angewandte Chemie, vol. 52, no 30, 2013, pp7822–7824; doi:
10.1002/anie.201302749.

23. Problems with scaffolds
• Definition of "scaffold" not consistent & rigorous
among chemists & cheminformaticians.
Testosterone
Estradiol
Danazol
Cyproterone
acetate
"We think in generalities, but we live in detail." - Alfred North Whitehead

24. http://en.wikipedia.org/wiki/Steroids
Steroidogenesis
[#8]~[#6;R1]~1~[#6;R1]~[#6;R1]~[#6;R2]~2~[#6;R2]~1
~[#6;R2]~[#6;R1]~[#6;R2]~1~[#6;R2]~2~[#6;R1]~[#6;R
1]~[#6;R2]~2~[#6;R1]~[#6;R1](~[#8])~[#6;R1]~[#6;R1]
~[#6;R2]~1~2
Steroid pattern
definition via
SMARTS
Problems solved by Cheminformatics

25. Conclusion:
Molecular scaffolds
(like cheminformatics itself)
are special and useful guides
for discovery
in chemical biology,
chemogenomics,
and drug discovery
ACS National Meeting - Sept. 8-12, 2013 - Indianapolis, IN
CINF Graduate Student Research Symposium in Cheminformatics, Information Science, and Library Science

26. Thank Yous:
Cristian Bologa, UNM
Tudor Oprea, UNM
Oleg Ursu, UNM
David Wild, IU
Gary Wiggins, IU
Happy Explorations!
ACS National Meeting - Sept. 8-12, 2013 - Indianapolis, IN
CINF Graduate Student Research Symposium in Cheminformatics, Information Science, and Library Science