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
hydrocortisone, etc. )
Wonder drugs and
What is a scaffold?
"Ring-system", "Ring", "Core", "Framework"
• Clustering, indexing databases.
• Navigation of chemical space.
• Data reduction, visualization.
What can be done with scaffolds?
Scaffold Hunter CARLSBAD
The Power to Explore Biological
Networks via Chemical Patterns
Badapple Promiscuity Plugin
(BioActivity Data Associative Promiscuity Pattern Learning Engine)
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.
Scaffolds & drug-scaffolds, the privileged few
explaining a lot of activity...
373,802 ; scaffolds:
146,024 ; assays: 528
“activity of DB” ~ # active scaffold-instances
• 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."
Problems with scaffolds
• Definition of "scaffold" not consistent & rigorous
among chemists & cheminformaticians.
"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)
Problems solved by cheminformatics
News: antibiotic scaffold:
• Cristian Bologa, UNM
• Tudor Oprea, UNM
• Oleg Ursu, UNM
• David Wild, IU
• Gary Wiggins, IU
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,
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".
Scaffolds are special
because: 3D shape