Computational based approaches for in silico screening and drug design will be a central theme of the network. For example, new theoretical methods are being developed including quantum chemical topology (Popelier) and biomolecular free energy (Henchman) [1-3]. Virtual screening and simulation techniques are being applied in the search for small molecule modulators of potassium ion channels (Sutcliffe) [4], human thymidine phosphorylase and c-Src signalling in colorectal cancer (Bryce, Freeman) [5]. Neglected diseases such as Chagas disease are also of interest and computational design approaches are developing new inhibitors of Trypanasoma cruzi trans-sialidase (TcTS) (Bryce) [6].

Bioinformatics and machine learning will help identify key properties of drug target proteins and to predict potential new targets (Doig). This approach could be very powerful if combined with chemoinformatic strategies for drug design, where we consider both drug and target together [7,8].

Small molecule libraries. Whilst computational studies, chemoinformatics and bioinformatics can help guide selection of targets and drug design, this can only be effective if small molecule libraries are generated and lead compounds are optimised efficiently. To this end the network relies on a large body of synthetic organic and biological chemists who can provide access to novel chemical entities and focused libraries (e.g. Clayden, Procter, Whitehead, Micklefield, Turner, Flitsch, Freeman, Gardiner, Berrisford). Natural products continue to inspire and provide scaffolds for drug design and there are extensive efforts ongoing to synthesise analogues of key natural product leads (Procter AZ & GSK) [9,10].

Chemoenzymatic approaches will be used to generate lead compounds. For example, the Centre of Excellence in Biocatalysis (CoEBio3, Turner, Micklefield, Scrutton, Flitsch) have engineered new enzymes to prepare key chiral intermediates  and precursors [11,12,13]. Biosynthetic engineering approaches are also being developed to generate modified “non-natural” products that are otherwise too complex for effective total synthesis, including antibiotics of the daptomycin and ramoplanin family (Micklefield) [14,15]. Also, with Biotica, new methods are being developed to activate the expression of the vast majority of secondary metabolite biosynthetic gene clusters, which remain cryptic (unexpressed under laboratory conditions) [16]. The synthetic and natural compounds we develop by these approaches form the basis for the chemical genetics, targeted and phenotypic screening efforts.

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