» Articles » PMID: 24964346

Synthetic Compounds from an in House Library As Inhibitors of Falcipain-2 from Plasmodium Falciparum

Abstract

Falcipain-2 (FP-2) is a key cysteine protease from the malaria parasite Plasmodium falciparum. Many previous studies have identified FP-2 inhibitors; however, none has yet met the criteria for an antimalarial drug candidate. In this work, we assayed an in-house library of non-peptidic organic compounds, including (E)-chalcones, (E)-N'-benzylidene-benzohydrazides and alkyl-esters of gallic acid, and assessed the activity toward FP-2 and their mechanisms of inhibition. The (E)-chalcones 48, 54 and 66 showed the lowest IC50 values (8.5 ± 0.8 µM, 9.5 ± 0.2 µM and 4.9 ± 1.3 µM, respectively). The best inhibitor (compound 66) demonstrated non-competitive inhibition, and using mass spectrometry and fluorescence spectroscopy assays, we suggest a potential allosteric site for the interaction of this compound, located between the catalytic site and the hemoglobin binding arm in FP-2. We combined structural biology tools and mass spectrometry to characterize the inhibition mechanisms of novel compounds targeting FP-2.

Citing Articles

Three Decades of Targeting Falcipains to Develop Antiplasmodial Agents: What have we Learned and What can be Done Next?.

Gonzalez J, Salas-Sarduy E, Alvarez L, Valiente P, Arni R, Pascutti P Curr Med Chem. 2023; 31(16):2234-2263.

PMID: 37711130 DOI: 10.2174/0929867331666230913165219.


Synthesis, antibiotic modifying activity, ADMET study and molecular docking of chalcone (E)-3-(2,4-dichlorophenyl)-1-(2-hydroxyphenyl)prop-2-en-1-one in strains of Staphylococcus aureus carrying MepA efflux pumps.

Rocha J, de Freitas T, da Cunha Xavier J, Pereira R, Pereira Jr F, Nogueira C Arch Microbiol. 2021; 204(1):63.

PMID: 34940944 DOI: 10.1007/s00203-021-02666-z.


In silico identification of noncompetitive inhibitors targeting an uncharacterized allosteric site of falcipain-2.

Gonzalez J, Salas-Sarduy E, Alvarez L, Barreto Gomes D, Pascutti P, Oostenbrink C J Comput Aided Mol Des. 2021; 35(10):1067-1079.

PMID: 34617191 DOI: 10.1007/s10822-021-00420-7.


Identification of Plasmodium dipeptidyl aminopeptidase allosteric inhibitors by high throughput screening.

Sanchez M, de Vries L, Lehmann C, Lee J, Ang K, Wilson C PLoS One. 2019; 14(12):e0226270.

PMID: 31851699 PMC: 6919601. DOI: 10.1371/journal.pone.0226270.


The complex of Plasmodium falciparum falcipain-2 protease with an (E)-chalcone-based inhibitor highlights a novel, small, molecule-binding site.

Machin J, Kantsadi A, Vakonakis I Malar J. 2019; 18(1):388.

PMID: 31791339 PMC: 6889325. DOI: 10.1186/s12936-019-3043-0.