Hydroxamic Acid Inhibitors Provide Cross-Species Inhibition of Plasmodium M1 and M17 Aminopeptidases
Autor: | Sandra Duffy, Peter J. Scammells, Peter M. Grin, Tess R. Malcolm, Georgina S. Butler, Vicky M. Avery, Leonardo Lucantoni, Christopher M. Overall, Sheena McGowan, Natalie B. Vinh, Nyssa Drinkwater, Michael Kassiou |
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Rok vydání: | 2018 |
Předmět: |
Plasmodium
Cell Survival Plasmodium vivax Drug Resistance Protozoan Proteins Hydroxamic Acids 01 natural sciences Aminopeptidases 03 medical and health sciences chemistry.chemical_compound Antimalarials Structure-Activity Relationship Catalytic Domain parasitic diseases Drug Discovery Structure–activity relationship Humans Protease Inhibitors Binding site 030304 developmental biology Metalloexopeptidase chemistry.chemical_classification 0303 health sciences Hydroxamic acid Binding Sites biology Chemistry Plasmodium falciparum biology.organism_classification 3. Good health 0104 chemical sciences Molecular Docking Simulation 010404 medicinal & biomolecular chemistry Enzyme HEK293 Cells Biochemistry Molecular Medicine Hemoglobin |
Zdroj: | Journal of medicinal chemistry. 62(2) |
ISSN: | 1520-4804 |
Popis: | There is an urgent clinical need for antimalarial compounds that target malaria caused by both Plasmodium falciparum and Plasmodium vivax. The M1 and M17 metalloexopeptidases play key roles in Plasmodium hemoglobin digestion and are validated drug targets. We used a multitarget strategy to rationally design inhibitors capable of potent inhibition of the M1 and M17 aminopeptidases from both P. falciparum ( Pf-M1 and Pf-M17) and P. vivax ( Pv-M1 and Pv-M17). The novel chemical series contains a hydroxamic acid zinc binding group to coordinate catalytic zinc ion/s, and a variety of hydrophobic groups to probe the S1' pockets of the four target enzymes. Structural characterization by cocrystallization showed that selected compounds utilize new and unexpected binding modes; most notably, compounds substituted with bulky hydrophobic substituents displace the Pf-M17 catalytic zinc ion. Excitingly, key compounds of the series potently inhibit all four molecular targets and show antimalarial activity comparable to current clinical candidates. |
Databáze: | OpenAIRE |
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