In silico, in vitro, X-ray crystallography, and integrated strategies for discovering spermidine synthase inhibitors for Chagas disease
Description
<jats:title>Abstract</jats:title><jats:p>Chagas disease results from infection by <jats:italic>Trypanosoma cruzi</jats:italic> and is a neglected tropical disease (NTD). Although some treatment drugs are available, their use is associated with severe problems, including adverse effects and limited effectiveness during the chronic disease phase. To develop a novel anti-Chagas drug, we virtually screened 4.8 million small molecules against spermidine synthase (SpdSyn) as the target protein using our super computer “TSUBAME2.5” and conducted <jats:italic>in vitro</jats:italic> enzyme assays to determine the half-maximal inhibitory concentration values. We identified four hit compounds that inhibit <jats:italic>T</jats:italic>. <jats:italic>cruzi</jats:italic> SpdSyn (TcSpdSyn) by <jats:italic>in silico</jats:italic> and <jats:italic>in vitro</jats:italic> screening. We also determined the TcSpdSyn–hit compound complex structure using X-ray crystallography, which shows that the hit compound binds to the putrescine-binding site and interacts with Asp171 through a salt bridge.</jats:p>
Journal
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- Scientific Reports
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Scientific Reports 7 (1), 6666-, 2017-07-27
Springer Science and Business Media LLC
