Molecular scaffolds are special
and useful guides for discovery
Jeremy Yang, UNM & IU
Cristian Bologa, UNM
David Wild, IU
...
Molecular scaffolds are special
and useful guides for discovery
Jeremy Yang, UNM & IU
Cristian Bologa, UNM
David Wild, IU
...
What is a molecular scaffold?
• "Ring-system"
• "Ring"
• "Core"
• "Framework"
Can you identify this famous scaffold?
Some famous scaffolds
beta – lactam
(penicillins,
cephalosporins )
Millions saved,
billions earned
steroid
(testosterone,
...
Scaffolds are special because:
3D shape
Estradiol
docked into
ER-α
(OpenEye
Fred, Vida)
Scaffold scholarship & software
• Bemis & Murcko, “Molecular
frameworks”, 1996.
• Lewell et al., “Drug rings
database”, 20...
• Clustering, indexing databases.
• Navigation of chemical space.
• Data reduction, visualization.
• R-group / SAR analyse...
Scaffold Applications: Scaffold Hunter
Interactive exploration of chemical space with Scaffold Hunter,
S Wetzel, K Klein, ...
Scaffold Applications: Scaffold Hopper
Scaffold Hopper, NCATS/NCGC, http://tripod.nih.gov,
http://tripod.nih.gov/files/ACS...
Scaffold Applications: CARLSBAD
CARLSBAD:
The Power to Explore Biological
Networks via Chemical Patterns
The CARLSBAD Data...
Scaffold Applications: Molecule Cloud
The Molecule Cloud - compact visualization of large collections of
molecules, P Ertl...
Scaffold Applications: Badapple
(BioActivity Data Associative Promiscuity Pattern Learning Engine)
Translational Informati...
See also my Badapple talk in CINF session "Integrative Chemogenomics Knowledge Mining Using NIH
Open Access Resources", Tu...
Scaffold software: UNM-Biocomp-HScaf
(Open-source Google Code project)
http://code.google.com/p/unm-biocomp-hscaf/
UNM Translational Informatics Public Web Apps:
http://pasilla.health.unm.edu/
Demo web app: HScaf
Scaffold analysis algorithm
• Remove non-linking chains
• Keep linking chains
• Keep atoms multiply-bonded to rings and ch...
HierS scaffold hierarchy
quinine
Bemis-Murcko
framework
scaffolds
Cheminformatics and scaffolds:
Relevant methods
• SSSR (Smallest Set of Smallest Rings)
• Canonicalization (e.g. Morgan, C...
More scaffold charms
• Patents, Markush, $$$.
• Lead discovery ~ scaffold discovery.
• Organic chemists like scaffolds.
• ...
Scaffolds & drug-scaffolds, the privileged few
explaining a lot of activity...
Dataset:
BARD,
MLSMR,
MLP HTS
Totals: compo...
Privileged scaffolds concept
Nature favors a few privileged scaffolds, a.k.a.
"privileged structures", for multiple recept...
News: antibiotic, scaffold:
Anthracimycin
Anthracimycin, a Potent Anthrax Antibiotic from a Marine-Derived Actinomycete,
K...
Problems with scaffolds
• Definition of "scaffold" not consistent & rigorous
among chemists & cheminformaticians.
Testoste...
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]~...
Conclusion:
Molecular scaffolds
(like cheminformatics itself)
are special and useful guides
for discovery
in chemical biol...
Thank Yous:
Cristian Bologa, UNM
Tudor Oprea, UNM
Oleg Ursu, UNM
David Wild, IU
Gary Wiggins, IU
Happy Explorations!
ACS N...
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Molecular scaffolds are special and useful guides to discovery

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

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Molecular scaffolds are special and useful guides to discovery

  1. 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. 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. 3. What is a molecular scaffold? • "Ring-system" • "Ring" • "Core" • "Framework" Can you identify this famous scaffold?
  4. 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. 5. Scaffolds are special because: 3D shape Estradiol docked into ER-α (OpenEye Fred, Vida)
  6. 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. 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. 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. 9. Scaffold Applications: Scaffold Hopper Scaffold Hopper, NCATS/NCGC, http://tripod.nih.gov, http://tripod.nih.gov/files/ACS_apr8_2013.pdf.
  10. 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. 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. 12. Scaffold Applications: Badapple (BioActivity Data Associative Promiscuity Pattern Learning Engine) Translational Informatics Public Webapps: http://pasilla.health.unm.edu/
  13. 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. 14. Scaffold software: UNM-Biocomp-HScaf (Open-source Google Code project) http://code.google.com/p/unm-biocomp-hscaf/
  15. 15. UNM Translational Informatics Public Web Apps: http://pasilla.health.unm.edu/ Demo web app: HScaf
  16. 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. 17. HierS scaffold hierarchy quinine Bemis-Murcko framework scaffolds
  18. 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. 19. More scaffold charms • Patents, Markush, $$$. • Lead discovery ~ scaffold discovery. • Organic chemists like scaffolds. • Scaffolds can be "privileged".
  20. 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. 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. 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. 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. 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. 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. 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
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