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doi:10.1126/science.271.5246.219. report new prediction models made up of physicochemical properties that shed light on effective chemical groups for synthetic antimalarial compounds and help with screening for novel antimalarial drugs. (2). Indeed, the resistance of malaria to chloroquine and other 4-aminoquinoline-based therapies, in addition to the antifolate combination sulfadoxine-pyrimethamine, has switched the spotlight on artemisinin-based combinations to achieve higher response rates (3, 4). However, rapidly spreading resistance of to artemisinin-based combinations has been reported, posing a global challenge for malaria control (5, 6). Thus, it is important to discover new antimalarial drugs, especially for countries where malaria is usually endemic. Recently, several new classes of antimalarials have entered clinical studies with patients with malaria, such as the fast-acting brokers KAF156 (7), cipargamin (8), and artefenomel (9), whereas ferroquine remains the only long-acting novel antimalarial in clinical development (10, 11). However, these drugs have not yet been approved, and no vaccine to help in the prevention, control, elimination, and eradication of malaria has been approved yet. Only one vaccine candidate, RTS,S/AS01, reached phase III clinical trials, with relatively low efficacy (13, 14). Therefore, there is an urgent need for the discovery and development of novel antimalarial chemotherapies for which there are no preexisting resistance mechanisms. At present, one of the most promising and ideal targets is usually interference with the parasite’s heme detoxification pathway, which is the target for some current antimalarial drugs, such as quinine, which is still efficacious against chloroquine-resistant (15,C19). Recently, inhibition of the heme detoxification pathway of the parasite has been highlighted as a target in several antimalarial screening Rabbit Polyclonal to RPL39 projects (20,C22). This target is based on the inhibition of hemozoin, which is a crystalline pigment produced by the malaria parasite as a result of the hemoglobin degradation process to protect it against the toxic heme produced as an end product of hemoglobin catabolism (23, 24). Hemozoin formation is usually a protective physiochemical process that needs parasite protein (25,C27) and/or food vacuole lipids or membranes (28, 29) for synthesis. Therefore, lipophilic detergents that mimic intraparasite conditions, like Nonidet P-40 and BN82002 Tween 20, can be used as surrogate substances for high-throughput screening (HTS) of novel antimalarials because they have the ability to promote the crystallization of heme (20, 30). This makes hemozoin inhibition suitable for research using HTS assays to build prediction models for novel antimalarial drugs. Recently, several studies used HTS and predicted models for -hematin, synthetic hemozoin, inhibitors. Sandlin et al. screened 144,330 and produced 530 hits, 171 of which were active against parasites: 73 hits had parasite 50% inhibitory concentrations (IC50s) of 5 M, and 25 hits had IC50s of 1 M (31). In addition, using physiochemical properties (22), we recently developed an model to predict drug-like compounds that possess antihemozoin activity. As previously suggested, prediction models possess advantages BN82002 for antimalarial design because other approaches, such as analog development based on existing brokers or natural products, mainly detect new antimalarials by chemical modifications of previously known compounds (32); however, new antimalarial compounds can be discovered by the prediction equation based on a well-known metabolic target. Thus, prediction models aid in the discovery of new chemical scaffolds. Moreover, specialized labware and expensive equipment are not required for these models, so millions of library compounds can be screened by using the prediction models. Also, the relationship between the compound’s properties and antihemozoin activity is usually interpreted from the prediction models. Therefore, we continued previous work by developing new prediction models BN82002 for novel antimalarial activities of hemozoin inhibitors using the physiochemical properties of these small chemical compounds. RESULTS antimalarial assay. A total of 224 compounds with hemozoin inhibitory activity (22) were selected for antimalarial assays. Among them, 30 compounds with 45% growth-inhibitory activity at a concentration of 10 M were further subjected to a dose-response assay to remove false-positive compounds from the initial screening (Fig. 1), resulting in.