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;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

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