Dear Colleagues

Welcome to the summer edition of our newsletter. Collaboration is part of our culture at Emerald, and in this spirit we hope you’ll plan to join us online for a new webinar series that we are launching this month. We think that topics like Fragment Screening, Structural Genomics, Membrane Proteins and others will provide the basis for interesting and informative discussion.

In this issue we’re also proud to share progress made by some of our collaborators and by the team involved in the Seattle Structural Genomics Center for Infectious Disease as we push toward the goal of depositing 500 novel structures in the Protein Data Bank to help inspire new therapies in this important area (see “Collaborations”).

We’d love to talk about collaborating to accelerate your leads development or biologics engineering project – just call our Business Development office at 206-780-8959.

Lance Stewart, CEO

New! WEBINAR SERIES

The Emerald webinar series will feature speakers who are recognized experts in their fields, drawn from our own staff, and from collaborators and the scientific community at large. We’re planning to build on themes that can’t be covered in one session (e.g., membrane proteins) and to cover timely and hot topics-of-the-day. We welcome your ideas and suggestions, so please drop a note to your host, Doug Davies, and let us know what you think.

Mark your calendars and click through for your e-registrations

August 16, 2011
11:00 – 11:50 AM PDT
Speaker: Douglas R. Davies, PhD, Senior Project Leader, Emerald BioStructures
Title: “Choosing a Library for Fragment Based Drug Discovery: Lessons Learned at Emerald BioStructures"

ABSTRACT:

Fragment Based Drug Discovery (FBDD) is a proven technology that has impacted the development of several clinical candidate compounds. Fragment screening libraries have smaller compounds and fewer entities than high throughput screening collections, resulting in more efficient sampling of chemical space. Success is highly dependent not only on the qualities of the fragment library itself but also on the screening methodologies employed. Emerald BioStructures began development of a novel, metabolome-inspired fragment library called Fragments of Life™ (FOL) in 2006. The library has grown to a collection of ~2000 small molecules that includes biaryl protein structure mimetics and a “diversity set” of chemically tractable non-metabolite molecules. We have learned valuable lessons through our use of the FOL library for screening by X-ray diffraction and STD-NMR against more than 25 unique targets, including infectious disease targets, metalloenzymes, viral proteins and integral membrane receptors. In this 45 minute webinar we will discuss the following:

• Selecting the right fragment library for your FBDD project
• Practical aspects of fragment library handling and cocktailing
• Evaluating a crystal form for fragment tractability
• Soaking vs. Co-crystallization of protein FBDD targets
• Using STD-NMR for pre-screening fragment collections

Register now!

September 20, 2011
11:00 – 11:50 AM PDT
Speaker: Lance Stewart, PhD, MBA, CEO, Emerald BioStructures; Co-PI for Seattle Structural Genomics Center for Infectious Disease
Title: “Novel Targets for Infectious Disease: Using Structural Genomics Collaborations to Address an Important Unmet Need”

ABSTRACT:

Through our work with the Seattle Structural Genomics Center for Infectious Disease (www.ssgcid.org) we have solved more than 360 structures in fewer than four years. The targets have been nominated primarily by the antibacterial community and the work is funded by NIAID, with a goal of producing at least 500 X-ray crystal structures of infectious disease protein targets by the end of 2012.The community nomination process establishes the basis for collaborative structure guided design of new anti-microbial agents to address unmet medical needs in this important area. In this webinar, we will present examples of community nominated structures together with information on how we have established a network of investigators and resources to pursue cost effective collaborative discovery or new small molecule antibiotic candidates with broad spectrum activity. SSGCID represents a powerful chimera of industry and academia applied to the problem of antibacterial drug discovery. Webinar attendees will benefit from discussing the scientific advances, successes and challenges of these new types of alliances with Emerald BioStructures CEO and co-PI, Lance Stewart.

October 18, 2011
11:00 – 11:50 AM PDT
Speaker: Peter Nollert, PhD, Project Leader & Director of Membrane Protein Technologies, Emerald BioStructures
Title: “GPCR Expression for Biophysical and Structural Studies”

November 15, 2011
11:00 – 11:50 AM PST
Speaker: Darren Begley, PhD, Project Leader & NMR Core Leader, Emerald BioStructures
Title: "Integrated Biophysical Screening and Collaborative Medicinal Chemistry for Drug Discovery"

Learn more and register at http://emeraldbiostructures.com/webinars

COLLABORATIONS

New Clinical Candidates
The Emerald team would like to congratulate some of our clients, whose compounds recently entered clinical trials. We’re proud to have provided structures that contributed to these new experimental therapies. Deciphera Pharmaceuticals and researchers at Tufts Medical Center, M.D. Anderson, and the University of Michigan developed DCC-2036, which is being tested for the treatment of a Gleevec-resistant form of leukemia; N30 Pharmaceuticals’ N6022 is being developed for the treatment of asthma; and RG3039 is being developed for the treatment of spinal muscular atrophy in trials sponsored by RepliGen Corporation in cooperation with Families of Spinal Muscular Atrophy.

360th Structure Solved in SSGCID
Emerald recently solved the 360th novel infectious disease protein crystal structure within the Seattle Structural Genomics Center for Infectious Disease (SSGCID), a collaboration with our colleagues at Seattle BioMed, the University of Washington, and Battelle Memorial Institute / Pacific Northwest National Laboratory. We are now solving 100+ crystal structures of novel infectious disease protein targets each year in this 5-year project, including several fragment and ligand bound target structures. SSGCID has already become one of the world’s most productive structural genomics projects, learn more about our involvement here.

CORPORATE UPDATES

Integrated NMR Services
Emerald has brought online our Varian Unity Inova 500 MHz spectrometer with autosampler and dedicated NMR staff to provide our clients with integrated NMR services to complement our core X-ray structure services. We can now offer ligand characterization and Fragment Screening using ligand-observe methods as well as strategic 1D/2D experiments for NMR-based drug design.

ChemDiv Collaboration
Emerald and ChemDiv recently announced a collaboration to co-market their research services. Both companies are highly accomplished CROs dedicated to helping our clients discover new therapies based on insights into the modulation of biological targets by small molecule ligands. The collaboration establishes a strategic relationship that allows ChemDiv’s clients to access Emerald’s structural biology expertise in solving challenging protein targets. Emerald’s clients can now benefit from the full range of ChemDiv’s medicinal chemistry services, screening libraries, and solutions for compound acquisition.

PUBLICATIONS

So far in 2011, Emerald staff has authored or co-authored the following publications:

Discovery of S-nitrosoglutathione reductase inhibitors: Potential agents for the treatment of asthma and other inflammatory diseases
Xicheng Sun, Jan W. F. Wasley, Jian Qiu, Joan P. Blonder, Adam M. Stout, Louis S. Green, Sarah A. Strong, Dorothy B. Colagiovanni, Jane P. Richards, Sarah C. Mutka, Lawrence Chun, and Gary J. Rosenthal - ACS Med. Chem. Lett., Article ASAP, (Web): March 11, 2011

Protein crystal structures determined at Emerald BioStructures have supported the advancement of collaborator N30’s N6022, which is currently in clinical development as a potential agent for the treatment of acute asthma. Their investigational new drug is the first GSNOR inhibitor to enter human clinical development.

Predicting the success of fragment screening by X-ray crystallography
Davies, D. R., Begley, D. W., Hartley, R. C., Staker, B. L., and Stewart, L. J. - Methods Enzymol 493 (2011), 91-114

Scientists from Emerald BioStructures were invited to write two chapters for this volume of Methods in Enzymology, entitled “Fragment Based Drug Design – Tools, Practical Approaches, and Examples.” In this chapter, a survey was conducted across 18 unique fragment-screening campaigns to analyze trends and establish methods for predicting success in fragment screening.

Fragment screening of infectious disease targets in a structural genomics environment
Begley, D. W., Davies, D. R., Hartley, R. C., Edwards, T. E., Staker, B. L., Van Voorhis, W. C., Myler, P. J., and Stewart, L. J. - Methods Enzymol 493 (2011), 533-556

This chapter provides a detailed protocol for conducting fragment-based screening by X-ray crystallography for the Seattle Structural Genomics Center for Infectious Disease (http://www.ssgcid.org). It also details two case studies that show the utility in conducting fragment screening within a structural genomics context, both to help annotate (or correct) putative protein function, and to generate novel starting points for drug design.

Unswitch-ABL drugs overcome resistance in chronic myeloid leukemia
Wayne W. Chan, 4, Scott C. Wise, Michael D. Kaufman, Yu Mi Ahn, Carol L. Ensinger, Torsten Haack, Molly M. Hood, Jennifer Jones, John W. Lord, Wei Ping Lu, David Miller, William C. Patt, Bryan D. Smith, Peter A. Petillo, Thomas J. Rutkoski, Hanumaiah Telikepalli, Lakshminarayana Vogeti, Tony Yao, Lawrence Chun, Robin Clark, Peter Evangelista, L. Cristina Gavrilescu, Katherine Lazarides, Virginia M. Zaleskas, Lance J. Stewart, Richard A. Van Etten, and Daniel L. Flynn - Cancer Cell, Volume 19, Issue 4, 12 April 2011, Pages 435-437

ABL inhibitors have revolutionized the clinical management of chronic myeloid leukemia, but the BCR-ABLT315I mutation confers resistance to currently approved drugs. Chan et al. show, in this issue of Cancer Cell, that switch-control inhibitors block BCR-ABLT315I activity by preventing ABL from switching from the inactive to active conformation.

SAD phasing using iodide ions in a high-throughput structural genomics
Jan Abendroth, Anna S. Gardberg, John I. Robinson, Jeff S. Christensen, Bart L. Staker, Peter J. Myler, Lance J. Stewart and Thomas E. Edwards
Journal of Structural and Functional Genomics 12 (2011), 83-95

We have adopted the use of iodide ion soaks and single wavelength anomalous dispersion (SAD) experiments as our primary method for de novo phasing. This method uses existing native crystals and in house data collection, resulting in rapid, low cost structure determination. Here we present a general overview of this method as well as several examples including SAD phasing of proteins with novel folds and the combined use of SAD and MR for targets with weak MR solutions.

Leveraging structure determination with fragment screening for infectious disease drug targets: MECP synthase from Burkholderia pseudomallei
Begley DW, Hartley RC, Davies DR, Edwards TE, Leonard JT, Abendroth J, Burris CA, Bhandari J, Myler PJ, Staker BL, Stewart LJ.
J Struct Funct Genomics 12(2):63-76. Epub 2011 Feb 26

A series of complex structures obtained with screening hits reveal distinct binding pockets and a range of small molecules which form complexes with the target. Additional soaks with these compounds further demonstrate a subset of fragments to only bind the protein when present in specific combinations. This ensemble of fragment-bound complexes illuminates several characteristics of MECP synthase, including a previously unknown binding surface external to the catalytic active site.

Crystal structure of a DNA containing the planar, phenoxazine-derived bi-functional spectroscopic probe Ç
Thomas E. Edwards, Pavol Cekan, Gunnar W. Reginsson, Sandip A. Shelke, Adrian R. Ferre-D’Amare, Olav Schiemann, Snorri Th. Sigurdsson
Nucleic Acids Research (2011) First published online: January 19, 2011

Scientists at Emerald BioStructures determined a high resolution crystal structure of a DNA containing a modified nucleotide that is a novel, bi-functional spectroscopic probe. The results stem from collaborations with the University of Iceland, the University of St. Andrews, and the Fred Hutchinson Cancer Research Center.

CONTACT US

Diana R. Wetmore, Ph.D.
Vice President of Business Development and Alliances
dwetmore@embios.com
206-780-8959

©2011 Emerald BioStructures. All rights reserved. CrystalReady, Fragments of Life, and Gene Composer are trademarks of Emerald BioStructures. Other trademarks are property of their respective owners