Drug discovery for neglected diseases: molecular target-based and phenotypic approaches.

Ian H Gilbert

doi:10.1021/jm400362b

Abstract

Drug discovery for neglected tropical diseases is carried out using both target-based and phenotypic approaches. In this paper, target-based approaches are discussed, with a particular focus on human African trypanosomiasis. Target-based drug discovery can be successful, but careful selection of targets is required. There are still very few fully validated drug targets in neglected diseases, and there is a high attrition rate in target-based drug discovery for these diseases. Phenotypic screening is a powerful method in both neglected and non-neglected diseases and has been very successfully used. Identification of molecular targets from phenotypic approaches can be a way to identify potential new drug targets.

Highlights

Neglected tropical diseases represent a significant health burden in large parts of the world
A significant number of academic groups have engaged in the basic biology, and a few groups have engaged in coordinated drug discovery, such as our own unit, the Drug Discovery Unit (DDU) at the University of Dundee
There is genetic evidence reported with Leishmania mexicana which suggested that CRK3 is essential for cell cycle progression and involved in the G2/M transition.[45,46]

Summary

■ INTRODUCTION

Neglected tropical diseases represent a significant health burden in large parts of the world. Work by the Fairlamb group has shown that knockout of TryS in T. brucei using a tetracycline conditional double knockout of the enzyme gives parasite death after about eight days Mice treated with these parasites and fed with tetracycline did not develop disease.[41] This is very strong genetic evidence for the validation of TryS as a drug target. There is genetic evidence reported with Leishmania mexicana which suggested that CRK3 is essential for cell cycle progression and involved in the G2/M transition.[45,46] To further validate the target, we carried out a screen against the Leishmania CRK3−CYC6 complex using our focused kinase set.[31] This led to identification of eight chemical series Three of these series were optimized to give high potency and high selectivity compared to mammalian cyclin dependent kinase 2−cyclin A. In the pharmaceutical industry, drug discovery is conducted using both target-based (protein) screens and phenotypic (cellular) screens

■ CONCLUSION

■ ACKNOWLEDGMENTS

■ REFERENCES