Achiral, Cheap, and Potent Inhibitors of Plasmepsins I, II, and IV

Boss, Christoph; Corminboeuf, Olivier; Grisostomi, Corinna; Meyer, Solange; Jones, Andrew F.; Prade, Lars; Binkert, Christoph A.; Fischli, Walter; Weller, Thomas; Bur, Daniel

doi:10.1002/cmdc.200600223

Cited by 53 publications

(62 citation statements)

References 27 publications

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“…Upon sorting the compounds according to median rank and visual inspection of the poses of the top 500 compounds, 19 of them were tested in a fluorogenic assay [18] with the enzyme in solution. Six of these 19 compounds are active at concentrations below 100 µM against PM I, PM II, and PM IV (compounds 1-6 in Table 3 and Figure 3).…”

Section: Inhibitor Discovery By Fragment-based Docking and Consensus mentioning

confidence: 99%

“…It was not possible, for example, to use the number of hydrogen-bonds between the compound and the protein as a filter since protein relaxation might promote formation of additional intermolecular hydrogen bonds. Moreover, it is not simple to treat water molecules at the protein surface, some of which can be involved in intermolecular hydrogen bonds [18]. Visual examination was used to discard high scoring compounds which nevertheless did not seem to be properly docked.…”

Section: Consensus Scoringmentioning

confidence: 99%

“…A previously described fluorogenic assay [18] was used for all compounds tested in this work. Table 2.…”

Section: Enzymatic Assaymentioning

confidence: 99%

“…The IC 50 values represent the average of two repetitions of a fluorogenic proteolysis assay [18]. The estimated error for this enzymatic assay is ±50%.…”

Section: Figure Legendsmentioning

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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Section: Inhibitor Discovery By Fragment-based Docking and Consensus mentioning

confidence: 99%

Section: Consensus Scoringmentioning

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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“…Plasmepsin II (PMII) 1SME [224]; 1LEE, 1LF2 [225]; 1LF3, 1LF4 [226]; 2BJU [227]; 2IGX, 2IGY [228]; 3F9Q [229]; 1M43 [230]; 1ME6 [231]; 1W6H, 1W6I [232]; 1XDH, 1XE5, 1XE6 [233] Plasmepsin IV (PMIV) 1LS5 [225] Proline racemase (PRACA) 1W61, 1W62 [234] Protein Kinase 5 (PK5) 1OB3, 1V0O, 1V0P [235] Protein tyrosine phosphatase 1 (PTP1) 3M4U [236] 4AZ1 [237] Pteridine reductase 1 (PTR1) 2XOX [238] 1E7W, 1E92 [239]; 1W0C [240]; 2BF7, 2BFA,2BFM, 2BFO, 2BFP [241]; 2QHX, 3H4V [242] 2C7V [243]; 2WD7, 2WD8, 3GN1, 3GN2 [244]; 2VZ0 [245]; 3BMC, 3BMN, 3BMO, 3BMQ, 3JQ6, 3JQ7, 3JQ8, 3JQ9, 3JQA, 3JQB, 3JQC, 3JQD, 3JQE, 3JQF, 3JQG [246]; 2X9N, 2X9G, 2X9V, 3MCV [247]; 2YHI [248] Pteridine reductase 2 (PTR2) 1MXF, 1MXH [249] Purine nucleoside phosphorylase (PNP) 1NW4, 1Q1G [250]; 2BSX, 1SQ6 [251]; 3ENZ [252] Pyridoxal kinase (PdxK) 3ZS7 [253] Pyruvate kinase (PYK)…”

Section: Brucei T Cruzimentioning

confidence: 99%

The Potential of Secondary Metabolites from Plants as Drugs or Leads against Protozoan Neglected Diseases—Part III: In-Silico Molecular Docking Investigations

Ogungbe

Setzer

2016

Molecules

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Malaria, leishmaniasis, Chagas disease, and human African trypanosomiasis continue to cause considerable suffering and death in developing countries. Current treatment options for these parasitic protozoal diseases generally have severe side effects, may be ineffective or unavailable, and resistance is emerging. There is a constant need to discover new chemotherapeutic agents for these parasitic infections, and natural products continue to serve as a potential source. This review presents molecular docking studies of potential phytochemicals that target key protein targets in Leishmania spp., Trypanosoma spp., and Plasmodium spp.

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Antimalarials

Smithson¹,

Guiguemde²,

Guy³

2010

Burger's Medicinal Chemistry and Drug Discovery

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While the treatment of malaria has until recently relied upon a small number of therapeutic agents with a few mechanisms of action, the past decade has seen a huge growth in the number of targets being addressed and new agents being pushed to the clinic. This chapter briefly reviews existing agents and close homologs in development and then carefully explores new targets and new chemotypes being developed.

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Achiral, Cheap, and Potent Inhibitors of Plasmepsins I, II, and IV

Cited by 53 publications

References 27 publications

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

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

The Potential of Secondary Metabolites from Plants as Drugs or Leads against Protozoan Neglected Diseases—Part III: In-Silico Molecular Docking Investigations

Antimalarials

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