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BioFocus e-update October 2011
3D fragments now available
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Capitalizing on our experience in surface plasmon resonance (SPR) screening and optimization of fragment hits, BioFocus has designed and synthesized a bespoke set of compounds that differentiate themselves from other commercially available fragment collections by exploring 3-dimensional shape-space. FRG04 - the 3D fragment collection - is available to buy, or to screen at BioFocus using label-free binding SPR, high concentration biochemical assay and protein/ligand crystallography.
Click here for further information on the fragment collection.
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Figure 1. Electrostatic potential map of an example 3-dimensionally biased fragment in a minimized conformation. The red and blue shading represent areas of negative and positive potential respectively.
New Natural Product offering
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July saw BioFocus reaffirm itself in the field of natural product services by signing a collaboration with InterMed Discovery (IMD).
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Through the collaboration, clients will have the opportunity to screen IMD’s natural product collection using BioFocus’ leading screening technologies, followed by the option to utilize the IMD lead discovery platform to deliver bioactive compounds. Clients will have access to a collection that offers:
- a total collection that contains 100,000 samples containing an estimated 750,000 compounds
- over 13,000 pure natural compounds, 40% of which are unpublished
- approximately 87,000 HTS-compatible sub-fractions
- products sourced from fungal, bacterial, plant and other sources
- a collection that is continuously enhanced
Request further information on our natural product offering.
Success in drug discovery
A CRO like BioFocus which engages in drug discovery for our clients has a number of success measures. Some are financial, as financially stable organizations give comfort to our cleints, suppliers and shareholders. However, the success measure most interesting to our clients is the number and quality of candidate medicines that BioFocus delivers. We can now report on one of the major drug discovery successes in which BioFocus has been engaged.
BioFocus and the not-for-profit organization: Institute for One WorldHealth (iOWH) revealed their collaboration in 2006. iOWH engaged BioFocus to perform the chemistry, screening and ADME studies in a partnership to design, make and test compounds that would be a cure for diarrhea, particularly diarrhea caused by cholera toxin. The particular biological target, the Cystic Fibrosis Transmembrane conductance Regulator (CFTR) is a chloride ion channel found in the lung and gut. In the lung (and in defective form) the channel is responsible for cystic fibrosis. In the gut (and when over-activated by cholera toxin) it causes unregulated outflow of ions (and water) – an adult can lose 40L of water per day in some cases. Death, particularly of infants, can occur within hours. Around two million people die from cholera-induced diarrhea every year.
With some early hit molecules emanating from the laboratories of UCSF (Professor A. Verkman) showing that the channel could be negatively modulated, the challenge was on to design and validate robust biochemical and cellular assays to evaluate compounds, and to turn the hit molecules into viable leads for progression to drugs. The ion channel biology expertise and a chemistry design team at BioFocus in Chesterford Park worked for three and a half years to generate molecules with in vivo activity and to get acceptable PK parameters. Many avenues were explored during the collaboration, including a very large HTS screen to search for new chemotypes. The work eventually revealed a clinical candidate iOWH032, a compound that has now gained IND approval for first-in-man administration. This was announced by iOWH on 1 March 2011.
This short article, by its size, cannot describe all the challenges that the teams had to overcome. BioFocus had to engage with many organizations besides iOWH – including the University of Pittsburgh in the USA and CROs in China. Some elements of the project have now been revealed, commencing with a poster presented by Kevin Doyle at the 21st International Symposium on Medicinal Chemistry in Brussels, Belgium, 5-9 September 2010. Details of the poster can be found on the BioFocus website.
The reception to the project success at the Hyderabad conference (India could of course be one of the major beneficiaries of this project) was incredibly supportive – I do not recollect BioFocus being named the “Mother Theresa of drug discovery”, before.
The iOWH provided coordination and direction from Eugenio de Hostos, Tue Nguyen and David Brown.
The BioFocus team was: Kevin Doyle, Graham Jones, Joanne Peach, Michael Russell, Stephen Penrose, Amanda Van de Poël, Carrie-Anne Molyneaux, Jackie Macritchie, Angus MacLeod, Sebastian Brückner, Joanne Shearer, David Cronk, Gary Clark, Alan Beresford, Ian Gowers, Simon Dowler, Richard Martin, Carmela Clark, Suzie Clarke, Scott Maidment and Matthew Gardener.
Chris Newton, Managing Director BioFocus
The structure of an important neutralizing antibody bound to its target protein influenza hemagglutinin
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Figure 2.
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Influenza has recently gained notoriety due to publicity surrounding the 2009 outbreak of swine flu, concerns about the potential for avian flu to develop into a major human pandemic, and the apparent limitations on the production and supply of strain-specific vaccinations to the most vulnerable. Multiple groups are attempting to develop a broad spectrum treatment that combats infection and spread of the virus. One of the more promising approaches is the development of antibodies that recognize and neutralize conserved features of the machinery these viruses use to infect, multiply, and spread between humans.
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In conjunction with Humabs, BioFocus is at the forefront of this effort by solving the structure of a broadly neutralizing antibody bound to its viral target protein, hemagglutinin; the results having recently been published in Science (Vol. 333, pp. 850-6) and the structure available in the Protein Data Bank (PDB ID: 3ZTN). The unique features of this structure will hopefully lead to the development of a vaccine that effectively treats many current and future strains of influenza.
Figure 2. Outlining the trimeric assembly of the hemagglutinin-antibody complex. The hemagglutinin subunits are illustrated as colored molecular surfaces, and the antibody chains shown as ribbons radiating out from the central hemagglutinin trimer.
Fluorescence lifetime assays - an attractive addition to the toolbox of screening technologies
Recently BioFocus announced its collaboration with Almac allowing BioFocus customers with compound screening and profiling requirements to access Almac’s FLEXYTE™ Fluorescence Lifetime Technology (FLT) assays. The integration of this assay technology complements BioFocus’ current target class capabilities, providing access to previously inaccessible epigenetic targets and offers alternative approaches to fragment based screens and profiling.
FLT has many benefits over other screening technologies – most importantly significantly reduced assay interferences. This advantage has shown to be specifically valuable for target classes like proteases, where often interference of compounds is limiting the value of a hit finding campaign when Fluorescence Intensity (FI) is used as the assay readout.
While biophysical assay technologies are typically used for the primary screening of fragment libraries, the high sensitivity and robustness of FLT assays makes them an attractive additional technology for fragment screening. While FLT does not allow the detection of non-functional binding events, it is employed for the identification and orthogonal verification of active and allosteric site binders.
A recent highlight has been the launch of FLT assays for Histone Methyltransferases (HMTs). HMTs are a target family which is currently studied with great interest in a number of therapeutic areas. Besides the use of radiometric assay formats there is currently a lack of established assay technology tools for primary as well as secondary screening. The major advantage of FLT for the HMTs lies in the assay format which does not require antibodies. BioFocus has demonstrated the use of FLT for G9a and is currently expanding the portfolio of assays within this exciting new field of drug discovery.
The development of further FLT based assays for additional target families, especially in the epigenetics field, is under way. With the experience we have gained in the field, BioFocus is ready to incorporate further FLT applications and develop assays for your novel and challenging next target.
Get in touch with us to learn more.
Our Science
BioFocus’ reputation for quality and reliability is due in part to its science driven people. Where possible we share our research and encourages interactive discussions through papers, poster presentations and webinars.
Scientific webinars – view our on demand webinars covering ADME and intelligent screening topics. The platform allows the viewer to ask the presenter questions through an online Q&A facility.
Poster presentations – view, read, download and distribute snippets of BioFocus research, results and technology application.
Publications - recent publications include: “A New Apo-Caspase-6 Crystal Form Reveals the Active Conformation of the Apoenzyme” a structural biology paper co-authored with members of the CHDI foundation and “A Comparative Study of Fragment Screening Methods on the p38 alpha Kinase: New Methods, New Insights”, a paper that demonstrates BioFocus’ strength of technology and its application.
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