Strategies & Tools for Therapeutic Discovery
Gareth Price,a,b Sophie Martucci,a,b,c Richard M Napier,b Donald R J Singer,c Paul C Taylor,a John Watkins,a,c Andrew Marsha
Department of Chemistry, bSchool of Life Sciences, cWarwick Medical School
University of Warwick, Coventry CV4 7AL a.marsh@warwick.ac.ukgo.warwick.ac.uk/marshgroup
a
Exploring multi-target pharmacological space offers new ways of understanding biological actives.
We develop and use wet-lab and dry-lab tools that enable us to develop potential therapeutics.
3. Open Discovery: exploring ligand – target space
2. Uncovering new targets: Magic Tag®
Expression and display of genomic cDNA libraries through T7 phage or phage-l
allows a significant portion of a cell’s proteome to be presented in a way that links
genotype to phenotype. We couple this with a straightforward photochemical
immobilisation to enable rapid and efficient screening against small bioactives
including therapeutics and plant hormones.
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A photoimmobilisation strategy that
maximises exploration of chemical space
in small molecule affinity selection and
target discovery: S J Dilly, M J Bell,
A J Clark, A Marsh, R M Napier, M J
Sergeant, A J Thompson, P C Taylor
Chem Commun 2007, 2808-2810.
Rapid identification of a putative
nteraction between β2-adrenoreceptor
agonists and ATF4 using a chemical
genomics approach: S R Ladwa, S J
Dilly, A J Clark, A Marsh, P C Taylor
ChemMedChem, 2008, 3, 742-744
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Starting from a SMILES representation of a known ligand for a receptor, we
used the ChemNProp server to select 50 similar compounds from PubMed
(>26M structures). OBabel was used for file conversion, conformer search and
energy minimisation. A python script generated a PDBQT file from the receptor
molecular structure using AutoDock Vina, adding partial charges and atom
types to the PDB format. Screening of the library produced a list of structures
sorted by energy output ready for clustering using tools such as AuPosSOM,
preparation for Amber MD, or direct visualisation and analysis.
opendiscovery.org.uk
The use of freely available and Open
Source tools for in silico screening in
chemical biology: G W Price, P S Gould,
A Marsh submitted for publcation
1. Network pharmacology and personalised medicines
Expanding the space shared between network pharmacology and medicine
requires us to recognise that many therapeutics are multi-target.
A I Hopkins Nat Chem Biol
2008, 4, 682-690
A chemical genomics approach to
identification of interactions between
bioactive molecules and alternative
reading frame proteins: P C Taylor, A J
Clark, A Marsh, D R J Singer, S J Dilly
Chem Commun, 2013, DOI: 10.1039/
c3cc44647f.
E A Ashley et al.
Lancet 2010, 375,
1525-1535
Personalized medicine - the impact on chemistry: J Watkins, A Marsh, P C Taylor,
D R Singer Therapeutic Delivery 2010, 1, 651-665.
4. Translational pharmacology
Calcium independent phospholipase A2β (iPLA2β) is linked to vascular
inflammation and contractility and of interest in hypertension and cardiovascular
disease. Few selective inhibitors of iPLA2β exist and in order to establish an
in vitro screen we have use the archetypal 43 kDa serine hydrolase patatin.
We are developing an improved homology model and have carried out Open
Discovery screens (box 3) to develop novel inhibitor space. We have access to
tissue samples for functional assays.
A new target for modulating human artery function: calcium-independent
phospholipase a2β modulates receptor-mediated contraction J Watkins, A Marsh,
A Shmygol, S James, W Dimitri, DRJ Singer Basic & Clinical Pharmacology &
Toxicology 2011, 109 Special Issue Supplement 1, 32.
(S)-Bromoenol lactone inhibitor bound in the
iPLA2β orthologue patatin active site using
Autodock Vina and Amber MD
Internal mammary artery
ring, mounted in an organ
bath chamber
Purification and inhibition studies of the calcium
independent phospholipase A2β orthologue patatin
isolated from Solanum tuberosum: S Martucci, A
Marsh, G W Price, D R J Singer, R Napier BPS
Pharmacology 2013.
Acknowledgements
Collaborators Andrew J Easton, Phillip S Gould, (School of LIfe Sciences), Wade Dmitri (University Hospital Coventry and Warwickshire), A Shmygol (Warwick Medical School),
Miquel Pons (University of Barcelona).
Suzanne J Dilly, Sweta Ladwa (Tangent Reprofiling Limited)
Funding: EPSRC, BBSRC, BPS, Tangent Reprofiling Limited, University of Warwick