Combining bioinformatics, cheminformatics, functional genomics and whole organism approaches for identifying epigenetic drug targets in Schistosoma mansoni

Publication date: Available online 13 November 2018Source: International Journal for Parasitology: Drugs and Drug ResistanceAuthor(s): Gilda Padalino, Salvatore Ferla, Andrea Brancale, Iain W. Chalmers, Karl F. HoffmannAbstractSchistosomiasis endangers the lives of greater than 200 million people every year and is predominantly controlled by a single class chemotherapy, praziquantel (PZQ). Development of PZQ replacement (to combat the threat of PZQ insensitivity/resistance arising) or combinatorial (to facilitate the killing of PZQ-insensitive juvenile schistosomes) chemotherapies would help sustain this control strategy into the future. Here, we re-categorise two families of druggable epigenetic targets in Schistosoma mansoni, the histone methyltransferases (HMTs) and the histone demethylases (HDMs). Amongst these, a S. mansoni Lysine Specific Demethylase 1 (SmLSD1, Smp_150560) homolog was selected for further analyses. Homology modelling of SmLSD1 and in silico docking of greater than four thousand putative inhibitors identified seven (L1 – L7) showing more favourable binding to the target pocket of SmLSD1 vs Homo sapiens HsLSD1; six of these seven (L1 – L6) plus three structural analogues of L7 (L8 – L10) were subsequently screened against schistosomula using the Roboworm anthelmintic discovery platform. The most active compounds (L10 - pirarubicin > L8 – danunorubicin hydrochloride) were subsequently tested against juvenile (3 wk old) and mature (7 wk old)...
Source: International Journal for Parasitology: Drugs and Drug Resistance - Category: Parasitology Source Type: research