Finding New Hits in Neglected Disease Projects: Target or Phenotypic Based Screening?

In this article, we discuss the merits of both target-based and phenotypic screening strategies to find starting points for drug discovery projects in neglected tropical disease including: human African trypanosomiasis, Chagas disease, leishmaniasis and malaria. Technological advances now mean that it is possible to undertake high quality screens against isolated molecular targets at considerable scale. However target selection is a minefield of potential issues and often molecules identified and developed as potent inhibitors of targets do not translate into actives against the whole parasite. The potential for rapid resistance development is also a key issue when tackling individual molecular targets. In phenotypic screening, compounds are screened against the whole organism, looking for activity without a priori knowledge of the target(s) being modulated. This approach brings the benefits of increased chances of efficacy and potentially slowed resistance development of a successful medicine but the lack of knowledge of the molecular target can make the optimisation process more challenging. Advances in screening technologies has now brought phenotypic approaches up to the scale attained by target-based approaches and we discuss opportunities for advances in this arena concluding that a robust drug discovery portfolio for such diseases should include both phenotypic and target-based approaches.