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Molecular Diversity: New Compounds for Research and Drug Discovery

Molecular Diversity
Reported by
Megan Stephan

Posted April 14, 2009


In recent years, diversity has been touted as an essential property of schools, companies, government, and other human endeavors. It is also important in the chemical world, because increasing the diversity of available chemical compounds improves our ability to discover biologically active molecules that can be used as drugs or research tools.

On February 26, 2009, researchers came together at the Academy to hear presentations on the creation and uses of chemical diversity. John Porco's group combines a high-throughput, combinatorial, parallel approach to the investigation of chemical reactions with intensive study of the reaction mechanisms and intermediates that result in interesting new compounds. R. Kiplin Guy narrated his decade-long quest to design new compounds that can be used to study the physiological roles of the thyroid hormone receptors. Daniel Erlanson provided an overview of a relatively new approach to generating chemical diversity, known as fragment-based ligand discovery.

Use the tabs above to find a meeting report and multimedia from this event.


Web Sites and Books

Web Sites

Center for Chemical Methodology and Library Development at Boston University
The Center for Chemical Methodology and Library Development at Boston University (CMLD-BU) is a new center funded by the National Institute of General Medical Sciences (NIGMS) focused on the discovery of new methodologies to produce novel chemical libraries of unprecedented complexity for biological screening.

Practical Fragments
Blog intended to promote discussion of fragment-based ligand discovery methods.

Fragment-Based Drug Discovery Literature
Blog that compiles literature and information from meetings about fragment-based ligand discovery.


Jahnke W, Erlanson, DA, eds. 2006. Fragment-based Approaches in Drug Discovery (Methods and Principles in Medicinal Chemistry). Wiley-VCH, Weinheim, Germany.


John Porco

Beeler AB, Su S, Singleton CA, Porco JA Jr. 2007. Discovery of chemical reactions through multidimensional screening. J. Am. Chem. Soc. 129: 1413-1419.

Kesavan S, Panek JS, Porco JA Jr. 2007. Preparation of alkylidene indane and related scaffolds and their further elaboration to novel chemotypes. Org. Lett. 9: 5203-5206.

Ong WW, Beeler AB, Kesavan S, et al. 2007. Nucleophilic addition to N-phosphinylimines by rare-earth-metal triflate/trifluoroacetic anhydride activation. Angew Chem. Int. Ed. Engl. 46: 7470-7472.

Peng LF, Kim SS, Matchacheep S, et al. 2007. Identification of novel epoxide inhibitors of hepatitis C virus replication using a high-throughput screen. Antimicrob Agents Chemother. 51: 3756-3759.

Yeager AR, Min GK, Porco JA Jr, Schaus SE. 2006. Exploring skeletal diversity via ring contraction of glycal-derived scaffolds. Org. Lett. 8: 5065-5068.

R. Kiplin Guy

Arnold LA, Kosinski A, Estébanez-Perpiñá E, et al. 2007. Inhibitors of the interaction of a thyroid hormone receptor and coactivators: preliminary structure-activity relationships. J. Med. Chem. 50: 5269-5280.

Arnold LA, Estébanez-Perpiñá E, Togashi M, et al. 2006. A high-throughput screening method to identify small molecule inhibitors of thyroid hormone receptor coactivator binding. Sci. STKE. Jun 27; 2006 (341): pl3.

Arnold LA, Estébanez-Perpiñá E, Togashi M, et al. 2005. Discovery of small molecule inhibitors of the interaction of the thyroid hormone receptor with transcriptional coregulators. J. Biol. Chem. 280: 43048-43055.

Estébanez-Perpiñá E, Arnold LA, Jouravel N, et al. 2007. Structural insight into the mode of action of a direct inhibitor of coregulator binding to the thyroid hormone receptor. Mol. Endocrinol. 21: 2919-2928.

Moore JM, Guy RK. 2005. Coregulator interactions with the thyroid hormone receptor. Mol. Cell Proteomics 4: 475-482.

Daniel Erlanson

Cancilla MT, He MM, Viswanathan N, et al. 2008. Discovery of an Aurora kinase inhibitor through site-specific dynamic combinatorial chemistry. Bioorg. Med. Chem. Lett. 18: 3978-3981.

Erlanson DA. 2006. Fragment-based lead discovery: a chemical update. Curr. Opin. Biotechnol. 17: 643-652.

Erlanson DA, Hansen SK. 2004. Making drugs on proteins: site-directed ligand discovery for fragment-based lead assembly. Curr. Opin. Chem. Biol. 8: 399-406.

Erlanson DA, McDowell RS, O'Brien T. 2004. Fragment-based drug discovery. J. Med. Chem. 47: 3463-3482.

Erlanson DA, Wells JA, Braisted AC. 2004. Tethering: fragment-based drug discovery. Annu. Rev. Biophys. Biomol. Struct. 33: 199-223.


Daniel A. Erlanson, PhD

Carmot Therapeutics, Inc.
e-mail | publications

In addition to co-editing the first book on fragment-based drug discovery, Daniel A. Erlanson is the inventor of several fragment-based drug discovery technologies, which he has used to discover leads against a variety of targets. Erlanson co-founded Carmot Therapeutics, a small molecule drug company using innovative lead-discovery techniques to target diseases of aging. Prior to Carmot, Erlanson spent a decade developing fragment-based drug discovery technologies at Sunesis Pharmaceuticals, where he worked since the company's inception in 1998. There, he also honed his medicinal chemistry skills on a variety of targets including proteases, phosphatases, and kinases.

Before joining Sunesis, Erlanson was an NIH postdoctoral fellow with James A. Wells at Genentech. He earned his PhD in chemistry from Harvard University in the laboratory of Gregory L. Verdine and his BA in chemistry from Carleton College in Northfield, Minnesota. Erlanson is an inventor on more than a dozen issued patents and published patent applications as well as an author of more than two dozen scientific publications.

R. Kiplin Guy, PhD

St. Jude Children's Research Hospital
e-mail | web site | publications

R. Kiplin Guy is currently chairman and member of the Department of Chemical Biology and Therapeutics at St. Jude Children's Research Hospital (SJCRH), Memphis, Tennessee. In 1996, Guy received his PhD in organic chemistry from the Scripps Research Institute (TSRI) La Jolla, CA. He also carried out additional training in physiology at the Woods Hole Research Institute during this period. From 1996 to 1998, he did a postdoctoral fellowship in cellular biology with Michael Brown and Joseph Goldstein at the University of Texas Southwestern Medical Center, Dallas, TX.

Guy has held academic positions at UCSF (assistant to full professor, currently adjunct professor), St. Jude Children's Research Hospital (member and chair), and Vanderbilt University (adjunct professor). His research is focused on the discovery and development of novel small molecules that target the pathophysiology of orphan pediatric diseases, particularly pediatric oncology and protozoal infectious diseases. Most of his group's work falls into the categories of chemical validation of novel targets, lead discovery and optimization of novel chemical matter for validated disease targets, and use of non-targeted whole-cell strategies for lead discovery and optimization. He is the author of 89 papers and book chapters, and the inventor on 9 issued patents.

John A. Porco, PhD

Boston University
e-mail | web site | publications

John Porco is professor of chemistry at Boston University and director of the Center for Chemical Methodology and Library Development at Boston University (CMLD-BU). He obtained his BA degree in 1985 from the College of the Holy Cross. He then moved to Yale (1986–1989) and Harvard University (1989–1992) where he earned his PhD under the direction of Stuart L. Schreiber. He worked on syntheses of the enediyne antibiotics. Porco was an NSF postdoctoral fellow with Chi Huey Wong at the Scripps Research Institute (1992–1994) where he studied carbohydrate chemistry. After his postdoctoral studies, Porco went on to work in venture capital (Avalon Ventures, La Jolla, CA) and industry as director of chemistry at Argonaut Technologies, which he co-founded in 1995.

Porco joined the Department of Chemistry at Boston University in 1999 as assistant professor and was promoted to professor in September 2004. In 2002, he successfully led an effort to establish the CMLD-BU. Funded by the National Institutes of Health (NIH) as a Center of Excellence, the focus of the CMLD-BU is the discovery of new methodologies to produce novel chemotypes and derived chemical libraries of unprecedented complexity for biological screening. In addition to multiple grants from the NIH, in 2001 Porco received the American Cancer Society Research Scholar Award for "Studies Towards the Synthesis of Torreyanic Acid and Related Epoxyquinoids" and, in 2003, the Bristol-Myers Squibb Unrestricted Grant in Synthetic Organic Chemistry. In 2009, Porco will receive the Arthur C. Cope Scholar Award from the American Chemical Society. Since beginning his research program at Boston University in 1999, he and his colleagues have published over 70 manuscripts in peer-reviewed journals and presented over 95 invited seminars at universities, pharmaceutical companies, and conferences.

Megan Stephan

Megan Stephan studied transporters and ion channels at Yale University for nearly two decades before giving up the pipettor for the pen. She specializes in covering research at the interface between biology, chemistry, and physics. Her work has appeared in The Scientist and Yale Medicine. Stephan holds a PhD in biology from Boston University.