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PDBsum entry 6ea2
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Hydrolase/hydrolase inhibitor
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PDB id
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6ea2
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References listed in PDB file
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Key reference
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Title
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Hydroxamic acid inhibitors provide cross-Species inhibition of plasmodium m1 and m17 aminopeptidases.
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Authors
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N.B.Vinh,
N.Drinkwater,
T.R.Malcolm,
M.Kassiou,
L.Lucantoni,
P.M.Grin,
G.S.Butler,
S.Duffy,
C.M.Overall,
V.M.Avery,
P.J.Scammells,
S.Mcgowan.
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Ref.
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J Med Chem, 2019,
62,
622-640.
[DOI no: ]
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PubMed id
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Abstract
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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.
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