Molecular scaffolds are special and useful guides to discovery
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Transcript of Molecular scaffolds are special and useful guides to discovery
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
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
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,
hydrocortisone, etc. )
Wonder drugs and hormones
benzodiazepine (Valium, flurazepam,
etc. )
“Mother’s little helper”
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.
• 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
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.
Scaffold Applications: Scaffold Hopper
Scaffold Hopper, NCATS/NCGC, http://tripod.nih.gov, http://tripod.nih.gov/files/ACS_apr8_2013.pdf.
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
Scaffold Applications: Molecule Cloud
The Molecule Cloud - compact visualization of large collections of molecules, P Ertl and B Rohde, J. Cheminfo, 2012, 4:12.
Scaffold Applications: Badapple (BioActivity Data Associative Promiscuity Pattern Learning Engine)
Translational Informatics Public Webapps: http://pasilla.health.unm.edu/
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
Scaffold software: UNM-Biocomp-HScaf (Open-source Google Code project)
http://code.google.com/p/unm-biocomp-hscaf/
Scaffold analysis algorithm • Remove non-linking chains • Keep linking chains • Keep atoms multiply-bonded to rings and chains • Special case: ignore solo-benzene.
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
More scaffold charms
• Patents, Markush, $$$. • Lead discovery ~ scaffold discovery. • Organic chemists like scaffolds. • Scaffolds can be "privileged".
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
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.
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.
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
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;R1]~[#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
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