{"doi":"10.3389/fphar.2020.00246","title":"Structure-Based Screening of Plasmodium berghei Glutathione S-Transferase Identifies CB-27 as a Novel Antiplasmodial Compound","abstract":"Plasmodium falciparum parasites are increasingly drug-resistant, requiring the search for novel antimalarials with distinct modes of action. Enzymes in the glutathione pathway, including glutathione S-transferase, show promise as novel antimalarial targets. This study aims to better understand the biological function of Plasmodium glutathione S-transferase, assess its potential as a drug target, and identify novel antiplasmodial compounds using the rodent model P. berghei. By using reverse genetics, we provided evidence that glutathione S-transferase is essential for survival of P. berghei intra-erythrocytic stages and is a valid target for drug development. A structural model of the P. berghei glutathione S-transferase (PbGST) protein was generated and used in a structure-based screening of 900,000 compounds from the ChemBridge Hit2Lead library. Forty compounds were identified as potential inhibitors and analyzed in parasite in vitro drug susceptibility assays. One compound, CB-27, exhibited antiplasmodial activity with an EC50 of 0.5 µM toward P. berghei and 0.9 µM toward P. falciparum multidrug-resistant Dd2 clone B2 parasites. Moreover, CB-27 showed a concentration-dependent inhibition of the PbGST enzyme without inhibiting the human ortholog. A shape similarity screening using CB-27 as query resulted in the identification of 24 novel chemical scaffolds, with six of them showing antiplasmodial activity ranging from EC50 of 0.6 – 4.9 µM. Pharmacokinetic and toxicity predictions suggest that the lead compounds have drug-likeness properties. The antiplasmodial potency, the absence of hemolytic activity, and the predicted drug-likeness properties position these compounds for lead optimization and further development as antimalarials.","journal":"Frontiers in Pharmacology","year":2020,"id":81001,"datarank":0.0,"base_score":0.0,"endowment":0.0,"self_citation_contribution":0.0,"citation_network_contribution":0.0,"self_endowment_contribution":0.0,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":14,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9551,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2020-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":419610,"name":"Daisy D. Colón-López","orcid":"0000-0002-3920-310X","position":1,"is_corresponding":false},{"id":379183,"name":"Joel Vega-Rodríguez","orcid":"0000-0002-9576-0058","position":2,"is_corresponding":false},{"id":421030,"name":"Alice Dupin","orcid":null,"position":3,"is_corresponding":false},{"id":107758,"name":"David A. Fidock","orcid":"0000-0001-6753-8938","position":4,"is_corresponding":false},{"id":419611,"name":"Abel Baerga‐Ortiz","orcid":"0000-0001-9487-1015","position":5,"is_corresponding":false},{"id":419612,"name":"José G. Ortíz","orcid":"0000-0003-1910-2528","position":6,"is_corresponding":false},{"id":419613,"name":"Jürgen Bosch","orcid":"0000-0002-2624-4105","position":7,"is_corresponding":false},{"id":419614,"name":"Adelfa E. Serrano","orcid":"0000-0001-5929-9973","position":8,"is_corresponding":false},{"id":421029,"name":"Emilee E. Colón-Lorenzo","orcid":null,"position":0,"is_corresponding":true}],"reference_count":66,"raw_metadata":null,"created_at":"2026-07-18T21:52:34.401799Z","pmid":"32256353","pmcid":null,"fwci":null,"citation_percentile":null,"influential_citations":0,"oa_status":null,"license":null,"views":0,"total_file_size_bytes":0,"version_count":0,"fair_f":null,"fair_a":null,"fair_i":null,"fair_r":null,"fair_zscore":null,"fair_rationale":null,"fair_model":null,"fair_agent_version":null,"fair_fulltext_source":null,"fair_has_llm":null,"fair_computed_at":null,"clinical_trials":[],"software_tools":[],"db_accessions":[],"linked_datasets":[],"topics":[]}