Computationally-guided drug repurposing enables the discovery of kinase targets and inhibitors as new schistosomicidal agents

Abstract

The development of novel therapeutics is urgently required for diseases where existing treatments are failing due to the emergence of resistance. This is particularly pertinent for parasitic infections of the tropics and sub-tropics, referred to collectively as neglected tropical diseases, where the commercial incentives to develop new drugs are weak. One such disease is schistosomiasis, a highly prevalent acute and chronic condition caused by a parasitic helminth infection, with three species of the genus Schistosoma infecting humans. Currently, a single 40-year old drug, praziquantel, is available to treat all infective species, but its use in mass drug administration is leading to signs of drug-resistance emerging. To meet the challenge of developing new therapeutics against this disease, we developed an innovative computational drug repurposing pipeline supported by phenotypic screening. The approach highlighted several protein kinases as interesting new biological targets for schistosomiasis as they play an essential role in many parasite’s biological processes. Focusing on this target class, we also report the first elucidation of the kinome of Schistosoma japonicum, as well as updated kinomes of S. mansoni and S. haematobium. In comparison with the human kinome, we explored these kinomes to identify potential targets of existing inhibitors which are unique to Schistosoma species, allowing us to identify novel targets and suggest approved drugs that might inhibit them. These include previously suggested schistosomicidal agents such as bosutinib, dasatinib, and imatinib as well as new inhibitors such as vandetanib, saracatinib, tideglusib, alvocidib, dinaciclib, and 22 newly identified targets such as CHK1, CDC2, WEE, PAKA, MEK1. Additionally, the primary and secondary targets in Schistosoma of those approved drugs are also suggested, allowing for the development of novel therapeutics against this important yet neglected disease.

Computational Chemogenomics Drug Repositioning Strategy Enables the Discovery of Epirubicin as a New Repurposed Hit for Plasmodium falciparum and P. vivax

“…We have previously developed an in silico target-based chemogenomics drug repurposing workflow ( 14 ), which led us to identify approved drugs with confirmed activity against the P. falciparum apicoplast ( 15 ), multiple life cycle stages of Schistosoma mansoni ( 16 , 17 ), paracoccidioidomycosis ( 18 ), Schistosoma sp. protein kinases ( 19 ), and Leishmania sp. kinases ( 20 ).…”

Precision medicine review: rare driver mutations and their biophysical classification

“…Phenotypic drug discovery is now considered in databases, with assays that it employs grouped by animal disease model or phenotypic endpoint, accounting for assay data on protein targets or cell- or tissue-based systems (Hunter et al 2018 ). Accounting for phenotypic consideration was also proposed to help computationally guided drug repurposing (Giuliani et al 2018 ). Phenotypic screens were also proposed to be useful in chemogenomics (Jacoby and Brown 2018 ), as well as bridging the gap between phenotypic and biochemical assays (Denny 2018 ).…”

“…Successful identification of drug candidates with either single cell or several cell types, as compared with targeted discovery, has reinvigorated phenotypic drug discovery (Giuliani et al 2018 ; Heilker et al 2018 ; Vaidya et al 2018 ). At first glance, the re-emergence of the phenotypic drug discovery discipline is anathema to genome-based precision drug discovery, where a panoply of mutations, or genomic aberrations, can be expressed by similar disease phenotypes at the cellular or organism level.…”

Drug targets for COVID-19 therapeutics: Ongoing global efforts

“…ABL) kinase is the target of Imatinib and the same was shown to be active against coronaviruses(Ananthula et al 2018;Coleman et al 2016;Giuliani et al 2018). (3)New target/new indication: This scenario occurs when an approved drug with a specific target is found to target additional viral proteins or targets.…”