【摘 要】
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Malaria still threatens global health seriously today.While the current discoveries of antima-larials are almost totally focused on single mode-of-action inhibitors,multi-targeting inhibitors are highly desired to overcome the increasingly serious drug re
【机 构】
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MOE Key Laboratory of Protein Sciences,School of Pharmaceutical Sciences,MOE Key Laboratory of Bioor
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Malaria still threatens global health seriously today.While the current discoveries of antima-larials are almost totally focused on single mode-of-action inhibitors,multi-targeting inhibitors are highly desired to overcome the increasingly serious drug resistance.Here,we performed a structure-based drug design on mitochondrial respiratory chain of Plasmodium falciparum and identified an extremely potent molecule,RYL-581,which binds to multiple protein binding sites of P.falciparum simultaneously(allosteric site of type Ⅱ NADH dehydrogenase,Qo and Qi sites of cytochrome bc1).Antimalarials with such multiple targeting mechanism of action have never been reported before.RYL-581 kills various drug-resistant strains in vitro and shows good solubility as well as in vivo activity.This structure-based strategy for designing RYL-581 from starting compound may be helpful for other medicinal chem-istry projects in the future,especially for drug discovery on membrane-associated targets.
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