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”

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”, 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/

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 chains • Special case: ignore solo-benzene.

HierS scaffold hierarchy

quinine Bemis-Murcko

framework

scaffolds

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

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