Molecular scaffolds poster
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Molecular scaffolds are special and useful guides to discovery, poster (36x54"). Presented at ACS National Meeting SciMix in Indianapolis, Sep 9, 2013.
![Molecular scaffolds are special and useful guides for discovery
Jeremy Yang1,2, Cristian Bologa1,David Wild2, and Tudor Oprea1
1UNM Translational Informatics Division, Dept. of Internal Medicine, Albuquerque, NM
2IU Cheminformatics & Chemogenomics Research Group, School of Informatics & Computing, Bloomington, IN
Some famous scaffolds
beta – lactam
(penicillins,
cephalosporins )
Millions saved,
billions earned
steroid
(testosterone,
hydrocortisone, etc. )
Wonder drugs and
hormones
diazepam
(Valium, flurazepam,
etc. )
“Mother’s little
helper”
What is a scaffold?
"Ring-system", "Ring", "Core", "Framework"
Estradiol
docked into
ER-alpha
(using
OpenEye
Fred and
Vida)
• Clustering, indexing databases.
• Navigation of chemical space.
• Data reduction, visualization.
Scaffold Applications
What can be done with scaffolds?
Scaffold Hunter CARLSBAD
CARLSBAD:
The Power to Explore Biological
Networks via Chemical Patterns
Badapple Promiscuity Plugin
(BioActivity Data Associative Promiscuity Pattern Learning Engine)
Badapple
Promiscuity Plugin
for BARD,
http://bard.nih.gov
Related ACS talk: "The Badapple Promiscuity Plugin for BARD: Evidence-based promiscuity scores", in CINF
session "Integrative Chemogenomics Knowledge Mining Using NIH Open Access Resources", Mon, Sept. 9,
10:45am, Rm. 140.
Scaffold analysis algorithm
• Remove non-linking chains
• Keep multiply-bonded atoms
• Special case: ignore solo-benzene.
quinine
Bemis-Murcko
framework
scaffolds
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
“activity of DB” ~ # active scaffold-instances
Scaffold Hopper
• R-group / SAR analyses.
• Bioactivity prediction.
• Promiscuity prediction.
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."[1]
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
"The only rules that really matter are these: what a man can do and what a man can't do." - Jack Sparrow
Scaffold software: UNM-Biocomp-HScaf
(Google Code project)
http://code.google.com/p/unm-biocomp-hscaf/
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
News: antibiotic scaffold:
Anthracimycin
Acknowledgements
• Cristian Bologa, UNM
• Tudor Oprea, UNM
• Oleg Ursu, UNM
• David Wild, IU
• Gary Wiggins, IU
References:
1. "Methods for drug discovery: development of potent, selective,
orally effective cholecystokinin antagonists", Evans et al., J. Med.
Chem., 1988, 31, 2235.
2. “The properties of known drugs. 1. Molecular frameworks”, G Bemis
& M Murcko, J Med Chem, 39, 2887-2893, 1996.
3. “Drug rings database with web interface. A tool for identifying
alternative chemical rings in lead discovery programs”, X Lewell, A
Jones, C Bruce, G Harper, M Jones, I McLay, J Bradshaw, J Med Chem,
46, 3257-3274, 2003.
4. “HierS: hierarchical scaffold clustering using topological chemical
graphs”, S Wilkens, J Janes, A Su, J Med Chem, 48, 182-193, 2005.
5. P Ertl, S Jelfs, J Muhlbacher, A Schuffenhauer, & P Selzer, “Quest for
the Rings”, J Med Chem, 49, 4568-4573, 2006.
6. "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.
7. Scaffold Hopper, NCATS/NCGC, http://tripod.nih.gov,
http://tripod.nih.gov/files/ACS_apr8_2013.pdf.
8. "The CARLSBAD Database: A Confederated Database of Chemical
Bioactivities", S Mathias, J Hines-Kay, J Yang, G Zahoransky-Kohalmi,
C Bologa, O Ursu & T Oprea, Database, 2013, bat044.
9. "Anthracimycin, a Potent Anthrax Antibiotic from a Marine-Derived
Actinomycete", K Jang et al., Ang Chemie, 52 (30), 2013, 7822–7824.
More scaffold charms
• Patents, Markush, $$$.
• Lead discovery ~ scaffold discovery.
• Organic chemists like scaffolds.
• Scaffolds can be "privileged".
Happy Explorations!
Scaffolds are special
because: 3D shape](https://image.slidesharecdn.com/molecularscaffoldsposter-130910145112-phpapp02/85/molecular-scaffolds-poster-1-320.jpg)
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Molecular scaffolds poster
- 1. Molecular scaffolds are special and useful guides for discovery Jeremy Yang1,2, Cristian Bologa1,David Wild2, and Tudor Oprea1 1UNM Translational Informatics Division, Dept. of Internal Medicine, Albuquerque, NM 2IU Cheminformatics & Chemogenomics Research Group, School of Informatics & Computing, Bloomington, IN Some famous scaffolds beta – lactam (penicillins, cephalosporins ) Millions saved, billions earned steroid (testosterone, hydrocortisone, etc. ) Wonder drugs and hormones diazepam (Valium, flurazepam, etc. ) “Mother’s little helper” What is a scaffold? "Ring-system", "Ring", "Core", "Framework" Estradiol docked into ER-alpha (using OpenEye Fred and Vida) • Clustering, indexing databases. • Navigation of chemical space. • Data reduction, visualization. Scaffold Applications What can be done with scaffolds? Scaffold Hunter CARLSBAD CARLSBAD: The Power to Explore Biological Networks via Chemical Patterns Badapple Promiscuity Plugin (BioActivity Data Associative Promiscuity Pattern Learning Engine) Badapple Promiscuity Plugin for BARD, http://bard.nih.gov Related ACS talk: "The Badapple Promiscuity Plugin for BARD: Evidence-based promiscuity scores", in CINF session "Integrative Chemogenomics Knowledge Mining Using NIH Open Access Resources", Mon, Sept. 9, 10:45am, Rm. 140. Scaffold analysis algorithm • Remove non-linking chains • Keep multiply-bonded atoms • Special case: ignore solo-benzene. quinine Bemis-Murcko framework scaffolds 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 “activity of DB” ~ # active scaffold-instances Scaffold Hopper • R-group / SAR analyses. • Bioactivity prediction. • Promiscuity prediction. 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."[1] 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 "The only rules that really matter are these: what a man can do and what a man can't do." - Jack Sparrow Scaffold software: UNM-Biocomp-HScaf (Google Code project) http://code.google.com/p/unm-biocomp-hscaf/ 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 News: antibiotic scaffold: Anthracimycin Acknowledgements • Cristian Bologa, UNM • Tudor Oprea, UNM • Oleg Ursu, UNM • David Wild, IU • Gary Wiggins, IU References: 1. "Methods for drug discovery: development of potent, selective, orally effective cholecystokinin antagonists", Evans et al., J. Med. Chem., 1988, 31, 2235. 2. “The properties of known drugs. 1. Molecular frameworks”, G Bemis & M Murcko, J Med Chem, 39, 2887-2893, 1996. 3. “Drug rings database with web interface. A tool for identifying alternative chemical rings in lead discovery programs”, X Lewell, A Jones, C Bruce, G Harper, M Jones, I McLay, J Bradshaw, J Med Chem, 46, 3257-3274, 2003. 4. “HierS: hierarchical scaffold clustering using topological chemical graphs”, S Wilkens, J Janes, A Su, J Med Chem, 48, 182-193, 2005. 5. P Ertl, S Jelfs, J Muhlbacher, A Schuffenhauer, & P Selzer, “Quest for the Rings”, J Med Chem, 49, 4568-4573, 2006. 6. "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. 7. Scaffold Hopper, NCATS/NCGC, http://tripod.nih.gov, http://tripod.nih.gov/files/ACS_apr8_2013.pdf. 8. "The CARLSBAD Database: A Confederated Database of Chemical Bioactivities", S Mathias, J Hines-Kay, J Yang, G Zahoransky-Kohalmi, C Bologa, O Ursu & T Oprea, Database, 2013, bat044. 9. "Anthracimycin, a Potent Anthrax Antibiotic from a Marine-Derived Actinomycete", K Jang et al., Ang Chemie, 52 (30), 2013, 7822–7824. More scaffold charms • Patents, Markush, $$$. • Lead discovery ~ scaffold discovery. • Organic chemists like scaffolds. • Scaffolds can be "privileged". Happy Explorations! Scaffolds are special because: 3D shape