ChEMBL

A number of you have asked for further details on the malaria postdoc project.... (details on how to apply, deadlines, etc can be found here).

Malaria remains one of the most significant causes of developing world mortality, and this global burden coupled with recent reports of parasites resistant to artemesinin, the most recently released anti-malarial, makes the search for new therapeutics an urgent priority. While the availability of multiple Plasmodium genome sequences has the potential to make a significant impact on malaria drug development, almost all previously successful therapies were empirically discovered and developed, and without a defined molecular target. Such entirely empirical-based discovery is now not considered practical, and so a hybrid approach of cell-based screening followed by target discovery for bioactive hit series is a compelling and practical way forward. Recently a number of very significant disclosures of HTS cell-based screening studies have occurred (see http://www.ebi.ac.uk/chemblntd). These data also typically have i) secondary assays to establish estimates of IC50 values, ii) cytotoxicity values against a human cell-line, and iii) a measure of compound ‘promiscuity’ (the propensity of a compound to be active in large number of assays, sometimes known as ‘frequent hitters’). Given that the compounds are cidal, and cell-penetrant, these datasets are highly valuable for future target and lead discovery for novel malaria therapies.

However, for these data, the precise molecular targets and mechanism of action are currently unknown, and a major challenge is in the identification of a target/mechanism of action for each compound/compound class. Once a specific target is known, it greatly simplifies future validation and compound optimisation, and also provides key insights into disease biology, pathogenesis, therapeutic index (TI), likelihood of resistance, and so forth.

The available postdoc position is multidisciplinary and highly collaborative and links computer-based target prediction and analysis along with experimental validation in order to identify potentially novel targets for the development of new and innovative anti-malarial therapies. The position will fund a postdoctoral position working jointly between two newly established groups, one (Overington, EMBL-EBI) with an expertise in chemoinformatics, drug discovery and lead optimisation, and the second (Rayner, Sanger) with expertise in malaria disease biology, genomics, experimental genetic manipulation and target discovery. Given the broad range of techniques required, we will provide training in any required areas.

The work will train a researcher in the principles of drug discovery as well as advanced molecular biology and genetic manipulation techniques in Plasmodium parasites, and will therefore give them a wide-ranging set of skills in the key future area of Chemical Biology.


The planned work programme is as follows:

• Clustering of compound series – each cluster will probably share a common mechanism of action.
  
• Selection of series for further detailed analysis.
  
• In silico prediction of molecular targets for selected compound clusters.
  
• Comparative genomic analysis of the predicted targets.
  
• in vitro validation of 40-50 predicted targets. This initial screen will be performed in the model organism P. berghei.
  
• In vitro validation of 5-10 high priority targets in P. falciparum parasites.
• For any validated targets, in vitro assays will be developed and structural collaborations explored to allow confirmation of binding/activity for selected targets.