Fragment screening against Schistosoma mansoni dihydroorotate dehydrogenase: a modern approach for drug discovery

Abstract

Fragment screening has emerged as an important tool in the pipeline of drug discovery. By using compounds of low molecular weight, it is possible to cover a broader range of the chemical space with fewer compounds. Fragments often bind with better ligand efficiencies than traditional screening and hits are capable of binding to a larger number of proteins than conventional 'drug-size' compounds. After the screening, results can be combined by growing, merging, or linking them to produce drug leads with higher affinity. This project focuses on the use of the fragment-based lead discovery technique to search for novel chemical entities as precursors of selective and potent inhibitors of Schistosoma mansoni dihydroorotate dehydrogenase (SmDHODH) with drug-like properties. Schistosoma mansoni is among the five species responsible for the schistosomiasis, a neglected parasitic disease caused by blood-dwelling trematodes of the genus Schistosoma. DHODH is a flavoenzyme that catalyzes the stereospecific oxidation of (S)-dihydroorotate (DHO) to orotate during the fourth and only redox step of the de novo pyrimidine nucleotide biosynthetic pathway. The depletion of nucleotide pools by the selective inhibition of DHODH has been exploited for the development of different therapeutic strategies, in particular to parasitic diseases. The present project represents a further step towards exploiting the inhibition of Schistosoma mansoni dihydroorotate dehydrogenase (SmDHODH) as a strategy to develop new therapeutics to fight schistosomiasis. (AU)