... understanding life in molecular detail

Dr Richard Foster

Small molecule drug discovery Medicinal chemistry, synthetic chemistry, Virtual drug design, Fragment-based design


Our group undertakes research in medicinal chemistry, synthetic chemistry and chemical biology.

Our group is highly multidisciplinary, with researchers working on chemical synthesis, computer-aided drug design, assay design and screening, on in vitro and in vivo systems, often undertaking work in collaboration with labs at University of Leeds, with industry and groups at universities across the UK.

The underlying focus of our research is small molecule drug discovery. Here we are interested in the identification and optimisation of small molecule modulators for a wide-range of target classes to support both the understanding of biological mechanism (pharmacological tool compounds) and as potential starting points for future drug discovery (hits and leads). We make use of a number of tools and technologies to support our research, including virtual drug design, high-throughput screening, fragment-based design as well as chemical proteomic approaches to manipulate and label proteins.

Current major projects include:
  • Design of small molecule inhibitors of the coagulation pathway
  • Synthesis of novel high relaxivity targeted contrast reagents
  • The application of fragment-based approaches to inhibitor design

Examples of current research projects:

Small molecule therapeutics: Various projects are underway to identify and optimise small molecule modulators of biological targets from a variety of target classes and therapeutic areas to support basic target validation (pharmacological tool compounds) and as potential starting points for future drug discovery (hits and leads).  Case studies:

  1. Development of a novel anticoagulant with minimal bleeding risk

We have identified potent, novel small molecule inhibitors of a key enzyme involved in regulation of the coagulation cascade with exceptional in vivo efficacy. The inhibitors have been identified by a number of parallel approaches incorporating virtual drug design, chemical synthesis and HTS of large drug-like small molecule libraries. Presently, we are optimising the inhibitors for target potency, specificity and drug-like physicochemical properties using iterative rounds of medicinal chemistry development and screening using a panel of orthogonal bioassays. Collaborators: Helen Philippou, Robert Ariens, Colin Fishwick

  1. Identification of novel inhibitors of TRP ion channel function as potential therapeutics

We have identified a series of novel inhibitors of a TRP ion channel implicated in cardioprotection. The compounds have been developed as agents to support detailed understanding of the role of the protein target and its relevance in disease as well for future development of small molecule-based therapeutics. These dual aims are being achieved through iterations of directed chemical synthesis aided by pharmacophore-based design and screening via a panel of orthogonal assays. Collaborators: Lin-Hua Jiang, David Beech, Rao Sivaprasadarao

Diagnostics: We are also working on several projects to identify chemical probes as diagnostics to monitor and modulate biological mechanisms, including the design of targeted contrast imaging agents for MRI and labeled probes to understand the complex signaling networks in disease pathways as well as targeted biosensors for possible point-of-care healthcare applications. Case studies.

  1. Targeted contrast agents

We are designing and synthesising modular targeted high relaxivity MRI contrast agents for protein targeted cardiovascular disease monitoring and prevention. Collaborators: Robin Bon, Stephen Gilbert, Sven Plein, Azhar Maqbool

  1. Electrochemical microarrays

We are developing a small molecule electrochemical microarray for detection of protein-small molecule binding interactions. We are designing multiplexed small molecule microarrays to detect binding of proteins by electrochemical impedance. This approach constitutes a highly promising and flexible method towards the label-free detection of small molecule-protein interactions and has a number of potential therapeutic and translational applications, including micro- HTS and point-of-care diagnostics. Collaborator: Stephen Johnson

Funding

Current research has been funded by the BHRC (Leeds), MRC, Parkinson’s UK, BHF, AICR, BBSRC, CRUK and NewLife.

Detailed research programme                  Close ▲
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Medicinal Chemistry and Chemical Biology Group Leader

Medicinal Chemistry Group Leader, Tripos, 1999-2008

Chemistry, 1.18
School of Chemistry
0113 3435759
r.foster@leeds.ac.uk

www.chem.leeds.ac.uk/People/Foster

Selected Publications

  1. Young LM, Saunders JC, Mahood RA, Revill CH, Foster RJ, Tu LH, Raleigh DP, Radford SE, Ashcroft AEScreening and classifying small-molecule inhibitors of amyloid formation using ion mobility spectrometry-mass spectrometry Nature Chemistry 7 73-81, 2015

  2. Foster TL, Thompson GS, Kalverda AP, Kankanala J, Bentham M, Wetherill LF, Thompson J, Barker AM, Clarke D, Noerenberg M, Pearson AR, Rowlands DJ, Homans SW, Harris M, Foster R, Griffin S Structure-guided design affirms inhibitors of hepatitis C virus p7 as a viable class of antivirals targeting virion releaseHepatology 59 408-422, 2014

  3. High-risk papillomavirus E5 oncoprotein displays channel-forming activity sensitive to small molecule inhibitors. J. Virol., 2012, 86, doi: 10.1128/JVI.06243-11

  4. Saunders JC, Young LM, Mahood RA, Jackson MP, Revill CH, Foster RJ, Smith DA, Ashcroft AE, Brockwell DJ, Radford SE An in vivo platform for identifying inhibitors of protein aggregation Nature Chemical Biology 12 94-101, 2016