WM382   Click here for help

GtoPdb Ligand ID: 11162

PDB Ligand Antimalarial Ligand
Compound class: Synthetic organic
Comment: WM382 is the drug-like lead for a novel class of antimalarial compounds that are dual inhibitors of P. falciparum plasmepsin IX (PfPMIX) and plasmepsin X (PfPMX). The compound was identified by an optimization study following phenotypic high-throughput screening of an aspartic protease inhibitor library [1].

The Malaria tab on this ligand page provides additional curator comments of relevance to the Guide to MALARIA PHARMACOLOGY.
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Ligand Activity Visualisation Charts

These are box plot that provide a unique visualisation, summarising all the activity data for a ligand taken from ChEMBL and GtoPdb across multiple targets and species. Click on a plot to see the median, interquartile range, low and high data points. A value of zero indicates that no data are available. A separate chart is created for each target, and where possible the algorithm tries to merge ChEMBL and GtoPdb targets by matching them on name and UniProt accession, for each available species. However, please note that inconsistency in naming of targets may lead to data for the same target being reported across multiple charts.

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View interactive charts of activity data across species
2D Structure
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2D Structure

An image of the ligand's 2D structure. For small molecules with SMILES these are drawn using the NCI/CADD Chemical Identifier Resolver. Click on the image to access the chemical structure search tool with the ligand pre-loaded in the structure editor. For other types of ligands, e.g. longer nucleotides and peptides, a manually drawn representation of the molecule may be provided.

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Physico-chemical Properties
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Physico-chemical Properties

Calculated molecular properties are available for small molecules and natural products (not peptides). Properties were generated using the CDK toolkit. All properties were selected to enable the prediction of the Lipinski Rule-of-Five profile or ‘druglikeness’ for each ligand. For more info on each category see the help pages.

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Hydrogen bond acceptors 6
Hydrogen bond donors 3
Rotatable bonds 6
Topological polar surface area 103.75
Molecular weight 504.27
XLogP 5.28
No. Lipinski's rules broken 1
SMILES / InChI / InChIKey
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SMILES / InChI / InChIKey

SMILES (Simplified Molecular Input Line Entry Specification) A specification for unambiguously describing the structure of chemical molecules using short ASCII strings. Canonical SMILES specify a unique representation of the 2D structure without chiral or isotopic specifications. Isomeric SMILES include chiral specification and isotopes.

Standard InChI (IUPAC International Chemical Identifier) and InChIKey InChI is a non-proprietary, standard, textual identifier for chemical substances designed to facilitate linking of information and database searching. An InChIKey is a simplified version of a full InChI, designed for easier web searching.

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Canonical SMILES CCC1(CC)NC(=N)N(C(=O)C1)[C@@H]1CCOc2c1cc(cc2)C(=O)N[C@H]1CC(C)(C)Oc2c1cccc2
Isomeric SMILES CCC1(CC)NC(=N)N(C(=O)C1)[C@@H]1CCOc2c1cc(cc2)C(=O)N[C@H]1CC(C)(C)Oc2c1cccc2
InChI InChI=1S/C29H36N4O4/c1-5-29(6-2)17-25(34)33(27(30)32-29)22-13-14-36-23-12-11-18(15-20(22)23)26(35)31-21-16-28(3,4)37-24-10-8-7-9-19(21)24/h7-12,15,21-22H,5-6,13-14,16-17H2,1-4H3,(H2,30,32)(H,31,35)/t21-,22+/m0/s1
InChI Key ZSZSSSHEMYULPX-FCHUYYIVSA-N
Bioactivity Comments
The interaction table below provides data from whole cell assays and gives the antiparasite activity of WM382 against a number of Plasmodium lifecycle stages. The compound demonstrates potent in vitro activity against P. falciparum (including multidrug-resistant strains) and P. knowlesi, with parasite development arrested at the late schizont form of the asexual blood stage [1].

Note: PfPMIX is not yet included in the database, with PfPMX tagged as the target for this ligand for data retrieval purposes.
Selectivity at other protein targets
Key to terms and symbols Click on species/strain names for details Click column headers to sort
Target Sp. Type Action Value Parameter Concentration range (M) Reference
Plasmodium falciparum plasmepsin X Pf

Plasmodium falciparum

P. falciparum (Pf) is one of five protozoan parasite species of the genus Plasmodium that cause malaria in humans. Pf is responsible for the majority of malaria related deaths and is the most prevalent species in sub-Saharan Africa.
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 None Inhibition 10.5 pKi - 1
⤷ pKi 10.5 (Ki 3.5x10-11 M) [1]
Description: Peptide cleavage assay using recombinant PMX
Whole organism assay data
Key to terms and symbols Click on species/strain names for details Click column headers to sort
MOA/likely target Sp. Assay description Type Action Value Parameter Concentration range (M) Reference
Plasmodium falciparum plasmepsin X Pk

Plasmodium knowlesi

P. knowlesi (Pk) is one of five protozoan parasite species of the genus Plasmodium that cause malaria in humans. This species of the parasite was originally identified as causing simian malaria but it is becoming a significant cause of zoonotic malaria and is an emerging public health issue in Southeast Asia. Pk has a 24-hour asexual replication cycle in erythrocytes and can progress quickly to severe clinical disease with fatal cases reported.
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 Parasite growth inhibition assay - - 9.7 pEC50 - 1
⤷ pEC50 9.7 (EC50 1.8x10-10 M) SYBR Green assay [1]
Lifecycle stages: Plasmodium asexual blood stage (erythrocytic merozoite, trophozoite, erythrocytic schizont)
Plasmodium falciparum plasmepsin X PfDd2

Plasmodium falciparum Dd2

P. falciparum strain Dd2 (PfDd2) is a clone derived from PfW2, following continuous culture in mefloquine. PfW2 was cloned from the Indochina III/CDC isolate, originally derived from a Laotian patient who failed chloroquine therapy.
PfDd2 can be obtained from the Malaria Research and Reference Reagent Resource Center (MR4) and is reported to be resistant to chloroquine, pyrimethamine and mefloquine.
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 Parasite growth inhibition assay - - 9.6 pEC50 - 1
⤷ pEC50 9.6 (EC50 2.6x10-10 M) [1]
Lifecycle stages: Plasmodium asexual blood stage (erythrocytic merozoite, trophozoite, erythrocytic schizont)
Plasmodium falciparum plasmepsin X Pf3D7

Plasmodium falciparum 3D7

P. falciparum strain 3D7 (Pf3D7) was derived from isolate NF54 by limiting dilution. The complete genome of Pf3D7 has been sequenced (GenBank: LN999946.1).
Pf3D7 can be obtained from the European Malaria Reagent Repository or the Malaria Research and Reference Reagent Resource Center (MR4) and is sensitive to a panel of antimalarial compounds including chloroquine and pyrimethamine.
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 Parasite growth inhibition assay - - 9.2 pEC50 - 1
⤷ pEC50 9.2 (EC50 6x10-10 M) Results are for R-WM382 [1]
Lifecycle stages: Plasmodium asexual blood stage (erythrocytic merozoite, trophozoite, erythrocytic schizont)
Plasmodium falciparum plasmepsin X PfK1

Plasmodium falciparum K1

P. falciparum strain K1 (PfK1) was isolated in Kanchanaburi, Thailand in 1979.
PfK1 can be obtained from the European Malaria Reagent Repository or the Malaria Research and Reference Reagent Resource Center (MR4) and is reported to be a multidrug-resistant strain.
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 Parasite growth inhibition assay - - 9.2 pEC50 - 1
⤷ pEC50 9.2 (EC50 6.5x10-10 M) [1]
Lifecycle stages: Plasmodium asexual blood stage (erythrocytic merozoite, trophozoite, erythrocytic schizont)
Plasmodium falciparum plasmepsin X Pf

Plasmodium falciparum

P. falciparum (Pf) is one of five protozoan parasite species of the genus Plasmodium that cause malaria in humans. Pf is responsible for the majority of malaria related deaths and is the most prevalent species in sub-Saharan Africa.
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 Standard membrane feeding assay (SMFA) - - - - - 1
⤷ Oocyst count: potent inhibition of oocyst development [1]
Lifecycle stages: Plasmodium mosquito host stage (gametocyte, gamete, zygote, ookinete, oocyst, sporozoite)