March 11, 2011
NMR spectroscopy and X-Ray crystallography synergistic techniques in fragment screening
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Complete Title: NMR spectroscopy and X-Ray crystallography synergistic techniques in fragment screening of infectious disease drug target documented in publication by Emerald researcher
BAINBRIDGE ISLAND, WA March 11, 2011 — The Journal of Structural and Functional Genomics has recently published an article by Darren Begley and other Emerald researchers entitled Leveraging structure determination with fragment screening for infectious disease drug targets: MECP synthase from Burkholderia pseudomallei. This paper documents fragment screening by nuclear magnetic resonance spectroscopy and X-ray crystallography, and demonstrates how both approaches can work together to identify novel chemical matter which binds the target enzyme. In this case, the target is MECP synthase, or IspF, an enzyme in a critical metabolic pathway for many infectious diseases which is absent in humans.
“The success of our fragment screening campaigns is significantly impacted by using multiple biophysical techniques,” said Darren Begley, Ph.D and head of the NMR facility at Emerald BioStructures. This dual approach has led to the identification of an ensemble of protein-ligand complexes, including fragments which only appear to bind in combination, and some which bind a new site external to the active site. This work was conducted as part of the Seattle Structural Genomics Center for Infectious Disease (www.ssgcid.org), and demonstrates the high-throughput structural genomics capabilities at Emerald to generate multiple ligand-bound structures of high priority drug targets from pathogenic organisms.
NMR at Emerald BioStructures
Known for innovative and high-throughput methods for X-ray crystallography, Emerald BioStructures has now added NMR spectroscopy to its biophysics and structural genomics offerings for drug discovery. With a 500 MHz Unity Inova system in place and Dr. Begley heading the NMR department, Emerald intends to utilize this instrument to conduct fragment screening campaigns and confirm protein-ligand binding interactions for its customers.
The role of MECP synthase in infectious disease
The enzyme MECP synthase (IspF; 2C-methyl-D-erythritol-2,4-cyclodiphosphate synthase) appears to be essential and highly conserved between malaria, tuberculosis and a variety of other pathogenic organisms. In this case, the enzyme is derived from Burkholderia pseudomallei, the gram-negative bacterium which causes the infectious disease melioidosis (also called Whitmore disease or Nightcliff gardener's disease) endemic to Thailand and northern Australia. The recently discovered biosynthetic pathway in which MECP synthase works has gained interest in academic laboratories and institutes looking for ways to develop new drugs which combat drug-resistant pathogens.
About Emerald BioStructures
Emerald BioStructures is an integrated gene-to-structure contract research organization that provides collaborative drug discovery services to pharmaceutical companies, biotechnology companies, academic institutions, and government facilities. The company operates a high-throughput platform leveraged for fragment-based lead discovery and structure-based drug design. Emerald’s work provides a solid foundation for the discovery of highly selective, efficacious drugs.
Contacts
Emerald BioStructures:
Lance Stewart, CEO
(206) 780-8911