Medicinal Chemistry
The Medicinal Chemistry group within the DivMCSB provides synthetic chemistry and bio-science expertise, which we apply to interdisciplinary drug discovery research projects in therapeutic areas of unmet medical need, especially cancer.
We are equipped for all conventional synthesis methodologies, including simultaneous multiple solution and solid-phase techniques, microwave-assisted synthesis, peptide synthesis, automated chromatographic purification, as well as a range of analytical techniques (UV-Vis, IR, MS, NMR; Infrastructure). Furthermore, we have biochemistry and cell biology facilities to develop and carry out a variety of screening assays, which are an integral part of our medicinal chemistry activities.
Structure-Guided Drug Design
The structural understanding at the atomic level of how specific molecules interact with one another is a powerful template in ligand design.
We use such information in the design and optimisation of drug-like small molecules with potency and specificity for our therapeutic targets. During the hit finding phase of a project we typically deploy receptor- and ligand-based virtual screening campaigns. Subsequently, hit-to-lead conversion and lead optimisation are informed iteratively through structural studies. During this process our synthetic chemists work closely with the Computational Modelling and Informatics and Structural Biology groups.
Apart from conventional targets such as enzymes (e.g. protein kinases) and GPCRs, we are especially interested in developing new drug design paradigms relevant for new to target classes, particularly protein–protein and oligonucleotide–protein interactions. Traditionally these targets, although they offer advantages in terms of potential drug selectivity and specificity, have been difficult to modulate with drug-like small molecules. We apply state-of-the art peptidomimetic and structure-guided design and synthesis methods to the synthesis and development of molecules that target so-called hot spot and allosteric sites that are implicated in the way that macromolecules interact.
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High Throughput Assay Technology
A reliable assay is required to measure the activity of compounds generated in medicinal chemistry programmes. The assay format will depend on the type of target under investigation. For some targets a biochemical assay format is preferred, for others a functional cell-based assay is more appropriate. Over the past years, several screening formats have emerged that are preferred for high throughput application. For biochemical assays these include resonance energy transfer (normal or time-resolved) and fluorescence polarization. We use these assay formats in support of our medicinal chemistry programmes.
Resonance energy transfer (RET). RET occurs when the emission spectrum of a fluorophore overlaps with the absorption spectrum of another molecule (usually another fluorophore). It is strictly dependent on the distance between the two molecules. We apply RET to measure the interaction between two protein partners. The two partners are labelled with suitable donor and acceptor groups. When proteins are not bound, not RET occurs due to the distance between the groups. When proteins are bound, RET can occur and protein interactions can be measured by determining the increase in acceptor fluorescence upon excitation of the donor.
Fluorescence polarisation (FP). FP relies on the principle that when excited by polarised light, a fluorescent molecule will emit light in the plane of polarisation. However, rotation of the molecule in solution will effectively depolarise emitted fluorescence. The degree of polarisation is dependent upon the size of the fluorescent molecule. Thus binding events can be assayed by measuring the degree of polarisation of the emitted light. This method requires the tracer molecule to be small in comparison to the partner molecule.
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Therapeutic Areas
Oncology. We adopt strategies for anticancer drug development that are aligned with modern mechanism- and structure-based design of targeted agents and we have recently initiated a number of new drug discovery projects, e.g.: inhibitors of translation initiation, chemotherapy directed against oncogene products of human papillomavirus, modulation of annexin complexes as a new antiangiogenic and antimetastatic therapeutic strategy, inhibitors of certain protein kinases closely associated with cancer, and design of inhibitors against particular protein interactions of tumour suppressor proteins. Our work is funded from various sources, including CRUK, AIRC, and industry. Nottingham has a long tradition of anticancer drug discovery, some of which is being developed through the spin-out company Pharminox Ltd (http://www.pharminox.com/).
Infection and Immunity. Derivatives of bacterial quorum sensing molecules (Phil. Trans. R. Soc. B. 2007, 362, 1119) have potential applications as new antimicrobial agents and as immunomodulators. We have collaborative projects underway that examine the medicinal chemistry of these concepts (MRC).
Neurodegenerative disease. We participate in collaborative projects aimed at targeted diagnosis and therapy (Nat. Rev. Drug Discov. 2007, 6, 464) of such disorders as Alzheimer's disease (Alzheimer's Research Trust, DTI/University Lachesis Fund).
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