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Identification and validation of P. berghei glutathione s‐transferase small molecule inhibitors by virtual library screening (LB274)

Antimalarial drug development is of outmost importance to achieve malaria eradication, especially by targeting the blood stages critical to parasite development. Identification and validation of potential drug targets is required for the development of novel antimalarials. Glutathione S‐transferase (GST) is a detoxification enzyme that has been associated with drug resistance and proposed as a potential drug target in Plasmodium. This study aims to elucidate the biological role of pbGST using a combination of reverse genetics and bioinformatics approaches. Multiple attempts to disrupt the pbgst gene were unsuccessful indicating that GST is essential for P. berghei erythrocytic stages; validating pbGST as a drug target. A pbGST structural model was generated by comparative modeling and used to perform a virtual library screening of the ChEMBL‐Neglected Tropical Disease library and the ChemBridge Express library using the OpenEye software suite. In silico screening identified several hits with potential as pbGST inhibitors. Docking analyses show favorable binding interactions between the small molecule compounds and the pbGST protein. P. berghei in vitro drug luminescence assay is being used to assess the antimalarial activity and the EC50 values of the identified compounds. This work should enhance our understanding on the role of Plasmodium GST and will be relevant for potential development of novel antimalarials.