... understanding life in molecular detail

Prof Colin Fishwick

Medicinal Chemistry, chemical biology, computer-assisted molecular design, synthetic chemistry


Fragment-based computational design coupled with synthesis is being used to identify novel small molecule protein ligands. In addition to their use as selective probes (e.g. via incorporation of fluorescent moieties), a number of these systems are also being progressed as therapeutic drug leads.

Current major projects include:
  • Metallo-Ã?-lactamase inhibitors: rescuing our current antibiotics
  • Dual-inhibition of DNA Gyrase and Topoisomerase IV
  • Inhibitors of Factor XIIIa as novel anti-thrombotics
  • DHODH inhibitors in the treatment of malaria

Metallo-ß-lactamase inhibitors: rescuing our current antibiotics

Metallo-β-lactamases play a key role in bacterial resistance to ß-lactam antibiotics by efficiently catalysing the hydrolysis of the ß-lactam amide bond. New Delhi metallo-ß-lactamase (NDM-1) is a broad spectrum ß-lactamase that is able to inactivate all ß-lactams except aztyeonam. NDM-1 was first identified in a Klebsiella pneumoniae isolated in Sweden from a patient who had previously been hospitalised in New Delhi. Since identification NDM-1 has spread across the world to countries such as Canada, Russia, and the UK.

Work within the group aims to identify novel inhibitors which could be co administered with current ß-lactam antibiotics to prolong the lifetime of ß-lactam antibiotics retaining the susceptibility of the bacteria to the ß-lactam antibiotics.

Dual-inhibition of DNA Gyrase and Topoisomerase IV

DNA Gyrase and Topoisomerase IV are bacterial type II topoisomerase enzymes responsible for manipulating the degree of supercoiling in DNA. These enzymes are established antibiotic targets; the flouroqiunolone antibiotics act by binding to the DNA binding region of the enzymes.


In this project we are attempting to identify potent inhibitors of the ATP binding site of these enzymes. The ATP binding site is located in the GyrB domain of DNA gyrase and the ParE domain of topoisomerase IV. Dual-inhibitors of these two targets would be good candidates as antibiotics as they will have a novel mode of action to any currently available antibiotics.

Inhibitors of Factor XIIIa as novel anti-thrombotics

Blood-clotting factor XIIIa (FXIIIa) is being investigated through the computer-based rational design of ligands, which are then synthesised and tested. This protein is involved in the final step in the formation of blood clots, greatly increasing their resilience to degradation. This makes FXIIIa a potential target for novel treatments of thrombosis; medications to prevent heart attack, stroke, pulmonary embolism and deep-vein thrombosis.

The novel compounds created as a part of this project are then tested for efficacy at the Leeds Institute for Genetics, Health and Therapeutics (LIGHT). Of particular interest is improving the selectivity for FXIIIa and against transglutaminase two and three (TG-2 and TG-3), two enzymes with very similar binding sites to FXIIIa.

DHODH inhibitors in the treatment of malaria

Malaria is a global problem. 50% of the world’s population is at risk of infection from the parasites which cause malaria. Resistance to all current chemotherapeutics used in the treatment of this illness has been observed and there is therefore, an urgent requirement for the development of novel chemotherapeutics to combat this disease, particularly against strains which have developed resistance to earlier therapies. Dihydroorotate dehydrogenase, the enzyme which catalyses the fourth step in de novo biosynthesis of pyrimidines, was previously shown to be an effective target for the development of novel chemotherapeutics. No drugs currently used in the treatment of this disease target this enzyme and therefore there is no previously observed resistance. Structure-based drug design methods are being applied to this enzyme resulting in the development of two novel and highly potent inhibitor series.

Targeting NS2 as a novel entry into the development of antivirals

Infection with Hepatitis C virus (HCV) delivers a positive sense single stranded RNA to the cellular cytoplasm which is subsequently translated into a single viral polyprotein. This polyprotein requires cleavage to liberate the viral proteins required for replication. The NS2 autoprotease performs one such essential cleavage event and represents an attractive target for novel direct acting anti-virals. We are using vHTS and structural information of NS2 to focus libraries and design compounds targeting the NS2 active site. Compounds are tested in a recently developed cell-based assay and in vitro biochemical assays to explore inhibition of autoproteolysis and activity against NS2-dependant HCV replication.

ENR inhibition: the development of a new range of anti-infectives

Enoyl-acyl carier protein reductase (ENR) is the final enzyme in the fatty acid biosynthesis pathway (FASII), responsible for the production of fatty acids in apicomplexan parasites and bacteria. Inhibition of ENR by small molecules is an effective point of therapeutic intervention as demonstrated by the natural product Triclosan which inhibits ENR and displays potent antibacterial and weak anti-parasitic activity. In our goal of discovering new and effective treatments of the infectious disease toxoplasmosis, we are using a structure-based approach to optimise inhibitors of Toxoplasma gondii ENR, currently in the hit-to-lead phase. Our work is in collaboration with crystallography groups at Sheffield (Professor David Rice) and Leeds (Dr Stephen Muench), microbiology groups at Johns Hopkins (Dr Sean Prigge), Strathclyde (Professor Craig Roberts) and Chicago (Dr Rice McLeod), funded by the National Institute of Health.

Detailed research programme                  Close ▲
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Professor of Medicinal Chemistry
PhD (liverpool)


Reader in Organic Chemistry, University of Leeds, 2006 - 2009
Honorary Reader in Medicinal Chemistry, University of Bradford, 2006 -
Honorary Professor of Medicinal Chemistry, University of Bradford 2009
Honorary Professor of Medicinal Chemistry, University of Sheffield 201

Chemistry G.52
School of Molecular and Cellular Biology
0113 343 6510
c.w.g.fishwick@leeds.ac.uk
http://www.chem.leeds.ac.uk/colin-fishwick/

Selected Publications

  1. N. Yi Mok, James Chadwick, Katherine A.B. Kellett, Eva Casas-Arce, Nigel M. Hooper, A. Peter Johnson and Colin W.G. Fishwick. Discovery of biphenylacetamide-derived inhibitors of BACE1 using de novo structure-based design methods. 2013, J. Med. Chem. 56, 1843-52.1. N. Yi Mok, James Chadwick, Katherine A.B. Kellett, Eva Casas-Arce, Nigel M. Hooper, A. Peter Johnson and Colin W.G. Fishwick. Discovery of biphenylacetamide-derived inhibitors of BACE1 using de novo structure-based design methods. 2013, J. Med. Chem. 56, 1843-52.

  2. Kerrie A. Smith, Richard J. Pease, Craig A. Avery, Jane M. Brown, Penelope J. Adamson, Robert A.S. Ariëns, Colin W.G. Fishwick, Helen Philippou, Peter J. Grant. Identification and Characterization of a Cryptic Binding site on Factor XIII A subunit for the Fibrinogen α chain and its functional role in clot stabilization. Blood, 2013, 121, 2117-26

  3. Paul T. P. Bedingfield, Deborah Cowen, Paul Acklam, Fraser Cunningham, Mark R. Parsons, Glenn A. McConkey, Colin, W. G. Fishwick, A. Peter Johnson. The Role of Inhibitor-Induced Structural Changes in the Selective Inhibition of Human- and Plasmodium Dihydroorotate Dehydrogenase. J. Med. Chem., 2012, 55, pp 5841–5850

  4. J Kankanala, A M Latham, A P Johnson, S Homer-Vanniasinkam, C W G Fishwick and S Ponnambalam. A combinatorial in silico and cellular approach to identify a new class of compounds that target VEGFR2 receptor tyrosine kinase activity and angiogenesis. B. J. Pharmacol., 2012, 166, 737–748