Fragment Screening in the Development of a Novel Anti-Malarial

Fragment-based approaches offer rapid screening of chemical space and have become a mainstay in drug discovery. This manuscript provides a recent example that highlights the initial and intermediate stages involved in the fragment-based discovery of an allosteric inhibitor of the malarial aspartate transcarbamoylase (ATCase), subsequently shown to be a potential novel anti-malarial. The initial availability of high-resolution diffracting crystals allowed the collection of a number of protein fragment complexes, which were then assessed for inhibitory activity in an in vitro assay, and binding was assessed using biophysical techniques. Elaboration of these compounds in cycles of structure-based drug design improved activity and selectivity between the malarial and human ATCases. A key element in this process was the use of multicomponent reaction chemistry as a multicomponent compatible fragment library, which allowed the rapid generation of elaborated compounds, the rapid construction of a large (70 member) chemical library, and thereby efficient exploration of chemical space around the fragment hits. This review article details the steps along the pathway of the development of this library, highlighting potential limitations of the approach and serving as an example of the power of combining multicomponent reaction chemistry with fragment-based approaches.