Novel Uncomplexed and Complexed Structures of Plasmepsin II, an Aspartic Protease from Plasmodium falciparum

Asojo, Oluwatoyin A.; Gulnik, Sergei V.; Afonina, Elena; Yu, Betty; Ellman, Jonathan A.; Haque, Tasir S.; Silva, Abelardo M.

doi:10.1016/s0022-2836(03)00036-6

Cited by 132 publications

(212 citation statements)

References 29 publications

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“…Plm II was chosen for the crystallization studies because it was easily obtainable in milligram quantities, and its crystallization conditions have been described previously. 17 Plm II mutant M205S was used, which displays enhanced resistance to self-cleavage compared to the wild type enzyme. 18 The obtained crystals diffracted to 1.85 Å resolution and belonged to space group C 2 with six molecules in the asymmetric unit.…”

Section: Espite Extensive Eradication Campaigns Malaria Caused Bymentioning

confidence: 99%

Plasmepsin Inhibitory Activity and Structure-Guided Optimization of a Potent Hydroxyethylamine-Based Antimalarial Hit

Jaudzems

Tars

Maurops

et al. 2014

ACS Med. Chem. Lett.

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Antimalarial hit 1SR (TCMDC-134674) identified in a GlaxoSmithKline cell based screening campaign was evaluated for inhibitory activity against the digestive vacuole plasmepsins (Plm I, II, and IV). It was found to be a potent Plm IV inhibitor with no selectivity over Cathepsin D. A cocrystal structure of 1SR bound to Plm II was solved, providing structural insight for the design of more potent and selective analogues. Structure-guided optimization led to the identification of structurally simplified analogues 17 and 18 as low nanomolar inhibitors of both, plasmepsin Plm IV activity and P. falciparum growth in erythrocytes.

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Section: Espite Extensive Eradication Campaigns Malaria Caused Bymentioning

confidence: 99%

Plasmepsin Inhibitory Activity and Structure-Guided Optimization of a Potent Hydroxyethylamine-Based Antimalarial Hit

Jaudzems

Tars

Maurops

et al. 2014

ACS Med. Chem. Lett.

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“…(PDB code 1LF3, [27]) was downloaded from the protein data bank [28]. This structure was chosen because of its slightly larger substrate-binding site, in particular at the S ′ 1 subpocket which has to accommodate the large P ′ 1 group of EH58.…”

Section: Preparation Of the Pm II Structurementioning

confidence: 99%

“…This structure was chosen because of its slightly larger substrate-binding site, in particular at the S ′ 1 subpocket which has to accommodate the large P ′ 1 group of EH58. In fact, EH58 cannot be docked into structures with a smaller S ′ 1 subpocket, e.g., the complex of PM II with the protease inhibitor pepstatin (PDB code 1LS5 [27]). The catalytic dyad was modeled with Asp 214 protonated and Asp 34 negatively charged, according to a previous MD study [29].…”

Section: Preparation Of the Pm II Structurementioning

confidence: 99%

“…Similarly, models of the complexes of PM II with compounds 9-12, 13 and 14 were generated using compound 11 as a template; the binding mode of the hydroxymethylamine inhibitor EH58 (PDB code 1LF3, [27]) was used as a template for all other compounds where crystal structures were not available. The coordinates of the inhibitors were refined by 100 steps of steepest descents and 10000 steps of conjugate gradients energy minimization.…”

Section: Liece Model For Pm IImentioning

confidence: 99%

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Discovery of Plasmepsin Inhibitors by Fragment‐Based Docking and Consensus Scoring

Friedman

Caflisch

2009

ChemMedChem

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Plasmepsins (PMs) are essential proteases of the plasmodia parasites and are therefore promising targets for developing drugs against malaria. We have discovered six inhibitors of PM II by high‐throughput fragment‐based docking of a diversity set of ∼40 000 molecules, and consensus scoring with force field energy functions. Using the common scaffold of the three most active inhibitors (IC50=2–5 μM), another seven inhibitors were identified by substructure search. Furthermore, these 13 inhibitors belong to at least three different classes of compounds. The in silico approach was very effective since a total of 13 active compounds were discovered by testing only 59 molecules in an enzymatic assay. This hit rate is about one to two orders of magnitude higher than those reported for medium‐ and high‐throughput screening techniques in vitro. Interestingly, one of the inhibitors identified by docking was halofantrine, an antimalarial drug of unknown mechanism. Explicit water molecular dynamics simulations were used to discriminate between two putative binding modes of halofantrine in PM II.

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“…The results of 22 independent MD runs, for a total simulation time of more than 0.45 ls are reported below. Four MD runs of PM II were started from the crystal structure of the apo enzyme (PDB: 1LF4 [15]). In two of these runs, D34 was protonated and D214 was negatively charged, while in the remaining two D214 was protonated and D34 was negatively charged.…”

Section: Introductionmentioning

confidence: 99%

The protonation state of the catalytic aspartates in plasmepsin II

Friedman

Caflisch

2007

FEBS Letters

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Assigning the correct protonation state to the catalytic residues is essential for a realistic modelling of an enzyme's active site. Plasmepsins are pharmaceutically relevant aspartic proteases involved in haemoglobin degradation by Plasmodium spp. In aspartic proteases, one of the two catalytic aspartates is protonated, while the other is negatively charged. Here, multiple explicit-water molecular dynamics simulations of plasmepsin II, uncomplexed and with a hydroxypropylamine peptidomimetic inhibitor, indicate that protonation of Asp214 favours a stable active site structure. Moreover, the protonation state of the catalytic aspartate has a strong influence on a linear chain of hydrogen bonds with the adjacent side chains.

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Novel Uncomplexed and Complexed Structures of Plasmepsin II, an Aspartic Protease from Plasmodium falciparum

Cited by 132 publications

References 29 publications

Plasmepsin Inhibitory Activity and Structure-Guided Optimization of a Potent Hydroxyethylamine-Based Antimalarial Hit

Plasmepsin Inhibitory Activity and Structure-Guided Optimization of a Potent Hydroxyethylamine-Based Antimalarial Hit

Discovery of Plasmepsin Inhibitors by Fragment‐Based Docking and Consensus Scoring

The protonation state of the catalytic aspartates in plasmepsin II

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