Opening the door to ligand-based drug discovery: a rapid and accurate technology for determining bioactive 3D molecular shapes
Submitting InstitutionUniversity of Manchester
Unit of AssessmentBiological Sciences
Summary Impact TypeTechnological
Research Subject Area(s)
Physical Sciences: Other Physical Sciences
Chemical Sciences: Theoretical and Computational Chemistry
Biological Sciences: Biochemistry and Cell Biology
Summary of the impact
A critical step in drug discovery is accurate determination of bioactive
3-dimensional structures of biologically-relevant molecules. Almond and
Blundell's proprietary method for analysing Nuclear Magnetic Resonance
(NMR) data has led to a world-first capability and establishment of the
company Conformetrix (renamed C4X Discovery in 2013). The platform
technology ('MolGyrate') is used to determine the dynamic
3-dimensional-conformation of biologically relevant molecules directly
from NMR data within weeks, compared with months to years for traditional
methods. C4X Discovery has secured substantial private investment (the
company has not disclosed the amount). In 2012 AstraZeneca began to apply
the technology across their entire pre-clinical therapeutic pipeline to
enhance lead discovery and hit identification.
The impact is based on research at the University of Manchester (UoM)
from 2005-2008. The key researchers were:
Dr Andrew Almond (Lecturer, 2005-date; co-founder of Conformetrix / C4X
Discovery Ltd.) Dr Charles Blundell (Post-Doctoral Research Associate,
2005-2008; co-founder of C4X Discovery Ltd.; Chief Scientist C4X Discovery
The researchers worked on carbohydrate 3D-conformation, which poses a
unique set of research problems given the high carbohydrate flexibility.
One strand of their research determined the molecular 3D-shape of the
flexible polysaccharide hyaluronan, which is distributed widely throughout
mammalian connective, epithelial, and neural tissues. Almond and Blundell
achieved this by performing computer simulations of the molecule in the
presence of aqueous solvent, preparing pure samples in the laboratory and
performing detailed experiments to validate the computational results
[1-5]. Prior hypotheses relating to assembly of hyaluronan (and hence
connective tissue) were based on a plastic space-filling molecular model;
the discovery of hyaluronan's accurate 3-dimensional shape and flexibility
has dramatically altered the understanding of extracellular matrix
Discovery and patent application
During their research on hyaluronan (2005-2008), Almond and Blundell
developed a quantitative theory that enabled raw NMR experimental data to
be used to calculate a quantified flexible structure of a hyaluronan
hexasaccharide without the need for inaccurate computer simulations. The
molecular 3D-shape of this molecule was resolved for the first time,
validating the new methodology on an inherently flexible biomolecule; a
world first. At this time it was realised that the nascent technological
breakthrough could be applied to any small flexible molecule , drugs
and peptides in particular. Using proof-of-concept funding from UoM, the
dynamic 3D-structures of several important molecules were resolved. A
UK-patent entitled, "Method for determining three- dimensional structures
of dynamic molecules," was filed in 2007 (applicants: Blundell CD and
Almond A; UK patent application number 0718027.6). The patent has reached
the National phase and applications have been filed in all major
References to the research
The research on hyaluronan has been published in international
biochemistry and chemistry journals.
1. Almond A, DeAngelis PL, Blundell CD. Dynamics of
hyaluronan oligosaccharides revealed by 15N relaxation.
J. Am. Chem. Soc. 2005; 127: 1086-1087. DOI:10.1021/ja043526i
2. Almond A, DeAngelis PL, Blundell CD. Hyaluronan: the
local solution conformation determined by NMR and computer modelling is
close to a contracted left-handed four-fold helix. J. Mol. Biol.
2006; 358: 1256-1269. DOI:10.1016/j.jmb.2006.02.077
3. Blundell CD, DeAngelis PL, Almond A. Hyaluronan: the
absence of amide-carboxylate hydrogen bonds and the chain conformation in
aqueous solution are incompatible with stable secondary and tertiary
structure models. Biochem. J. 2006; 396: 487-498.
4. Blundell CD, Reed MA, Almond A. Complete assignment of
hyaluronan oligosaccharides up to hexasaccharides. Carbohydr. Res.
2006; 341: 2803-2815. DOI:10.1016/j.carres.2006.09.023
5. Blundell CD, Almond A. Enzymatic and chemical methods for the
generation of pure hyaluronan oligosaccharides with both odd and even
numbers of monosaccharide units. Anal. Biochem. 2006; 353:
6. Blundell CD, Packer MJ, Almond A. Quantification of
free ligand conformational preferences by NMR and their relationship to
the bioactive conformation. Bioorg. Med. Chem. 2013; 21:
Details of the impact
Methods of determining small biological molecule 3D-conformation for use
in structure-based design have numerous limitations:
- protein co-crystallography for a novel target is very expensive and
can take years of trial and error
- the anhydrous packing environment in small molecule crystals leads to
- the theoretical nature of computational modelling leads to unreliable
- NMR methods cannot account for flexibility without resorting to
inaccurate computational chemistry
The MolGyrate technology overcomes these limitations, bringing accurate,
experimentally- determined solution structures (which relate directly to
the bioactive conformation ) to the market. This method has proven
capable of producing accurate bioactive structures for natural ligands,
performing rapid hit identification and removing bottlenecks in lead
optimisation, accelerating medicinal chemistry, reducing costs and
increasing productivity. To illustrate:
- C4X Discovery determined the flexible structure of carazolol in a
week, validating it to have the same shape as in the 03b22-adrenergic
- The company also solved an antagonist of the Class B GPCR
corticotropin-releasing factor receptor in the same time frame. It is
successfully using this approach to develop novel selective inhibitors
of the orexin-1 receptor, with potential to treat anxiety and addiction.
Pathways to impact
The technology was taken from the laboratory to a spin-out company
through research by Almond and Blundell (via research, translational and
proof-of-concept funding and a secondment from UoM). A prototype was
developed using BBSRC Follow-on funding (for demonstration to investors
and pharmaceutical clients). The drafting of a business plan was enabled
by a BBSRC/RSE Enterprise Fellowship awarded to Almond in 2007.
Conformetrix was assigned IP from the UoM and incorporated in 2007 (its
name changed to C4X Discovery in 2013).
Reach and significance of the impact
During the impact period the success of C4X Discovery and the
underpinning research, which includes a research collaboration with
AstraZeneca (AZ) across its pre-clinical therapeutic pipeline, have been
recognised through a series of awards: Bionow Start Up Company of the
Year (2008), NorthWest Development Agency GRAND award for Innovative
R&D (2009), and Bionow Emerging Biomedical Technology Project of the
Year (2011). Almond was also a finalist in the BBSRC Innovator of the
Year competition (2009) [A], and the company is profiled in a BBSRC
Impact Evidence Report (2012) [B]. More recently, the UoM and UoM IP
were joint runners-up in the 2013 BBSRC Fostering Innovation `Activating
Impact' Awards (with C4X Discovery being one of two examples).
Formation of a successful spin-out company:
Since 2008 C4X Discovery has raised several £million in venture capital
funding (specific amount not disclosed due to commercial
confidentiality), through a series of investments from Aquarius Equity
Partners [C], a fund focussed on UK life science technology.
In September 2012, Aquarius Equity Partners announced the release of a
third tranche of investment, triggered by significant progress of the
company against milestones. [text removed for publication].
Industry investment in R&D through in-house evaluation
C4X Discovery has provided paid services to the world's largest
pharmaceutical and biotech companies (not disclosed due to commercial
confidentiality). [text removed for publication].
Collaborative agreement with AstraZeneca to enhance drug
discovery and optimisation:
In 2012 C4X Discovery announced a two-year research collaboration
agreement with AZ, under which MolGyrate will be applied across AZ's
entire pre-clinical therapeutic pipeline to enhance lead discovery and
hit identification. The VP and Head of Discovery Sciences at AZ said:
"We are excited to be working with Conformetrix. We believe their
technology will provide a powerful addition to our hit identification
and lead optimisation approaches, supporting our strategic objectives
to improve the quality and choice of candidate compounds for our early
Also in BioCentury, a US-based biotech business newsletter, he
"As we've done due diligence, we've been looking to see if there is
anything else out there that competes with Conformetrix's technology,
and we feel it is truly unique" [E].
The collaborative agreement with Conformetrix forms part of a revamped
business development strategy for AZ [F]. The research collaboration is
one of only two involving companies/groups in Europe (and the only UK
deal, the majority being US-based ventures) and involves a team drawn
from both companies to manage the research strategy [G]. C4X Discovery
received an undisclosed upfront payment and research funding, and is
eligible for funding milestones as certain targets are met.
Sources to corroborate the impact
A. BBSRC Innovator of the Year 2009: Andrew Almond (finalist): http://www.bbsrc.ac.uk/web/FILES/Publications/innovator_2009.pdf
B. BBSRC Impact Evidence Reports 2012: Conformetrix
of support from a Director at Aquarius Equity Partners, confirming
investments into C4X Discovery.
D. Conformetrix and AstraZeneca sign collaborative agreement.
AstraZeneca Global, 16 April 2012: http://www.astrazeneca.com/Research/news/Article/16042012--conformetrix-and-astrazeneca
E. Confirming conformations. BioCentury: The Bernstein Report on
BioBusiness, 30 April 2012.
F. Racing to rebuild AZ. BioCentury: The Bernstein Report on
BioBusiness, 5 November 2012.
G. AstraZeneca boosts structure-activity R&D with Conformetrix's
new NMR-based approach. "The Pink Sheet" Daily, 16 April 2012.