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Biochim Biophys Acta Gen Subj. 2018 Dec;1862(12):2911-2923. doi: 10.1016/j.bbagen.2018.09.015. Epub 2018 Sep 22.

Identification of (4-(9H-fluoren-9-yl) piperazin-1-yl) methanone derivatives as falcipain 2 inhibitors active against Plasmodium falciparum cultures.

Author information

1
Departamento de Física, Universidade Estadual Paulista (UNESP), São José do Rio Preto, São Paulo CEP 15054-000, Brazil.; Computational Biology and Biomolecular Dynamics Laboratory, Center for Protein Studies, Faculty of Biology, University of Havana, Havana, Cuba.
2
Instituto de Investigaciones Biotecnológicas - Instituto Tecnológico de Chascomús (IIB-INTECH), Universidad Nacional de San Martín (UNSAM) - Consejo Nacional de Investigaciones Científicas y Técnicas (CONICET), San Martín, Buenos Aires, Argentina.
3
Grupo de Malaria, Facultad de Medicina, Universidad de Antioquia, Medellín, Colombia.
4
Departamento de Física, Universidade Estadual Paulista (UNESP), São José do Rio Preto, São Paulo CEP 15054-000, Brazil.
5
Laboratório de Dinâmica e Modelagem Molecular, Instituto de Biofísica Carlos Chagas Filho, Universidade Federal do Rio de Janeiro, Ave. Carlos Chagas Filho, 373, CCS-Bloco D sala 30, Cidade Universitária Ilha de Fundão, Rio de Janeiro CEP 21941-902, Brazil.
6
Computational Biology and Biomolecular Dynamics Laboratory, Center for Protein Studies, Faculty of Biology, University of Havana, Havana, Cuba. Electronic address: valiente@fbio.uh.cu.

Abstract

BACKGROUND:

Falcipain 2 (FP-2) is the hemoglobin-degrading cysteine protease of Plasmodium falciparum most extensively targeted to develop novel antimalarials. However, no commercial antimalarial drugs based on FP-2 inhibition are available yet due to the low selectivity of most FP-2 inhibitors against the human cysteine proteases.

METHODS:

A structure-based virtual screening (SVBS) using Maybridge HitFinder™ compound database was conducted to identify potential FP-2 inhibitors. In vitro enzymatic and cell-growth inhibition assays were performed for the top-scoring compounds. Docking, molecular dynamics (MD) simulations and free energy calculations were employed to study the interaction of the best hits with FP-2 and other related enzymes.

RESULTS AND CONCLUSIONS:

Two hits based on 4-(9H-fluoren-9-yl) piperazin-1-yl) methanone scaffold, HTS07940 and HTS08262, were identified as inhibitors of FP-2 (half-maximal inhibitory concentration (IC50) = 64 μM and 14.7 μM, respectively) without a detectable inhibition against the human off-target cathepsin K (hCatK). HTS07940 and HTS08262 inhibited the growth of the multidrug-resistant P. falciparum strain FCR3 in culture (half-maximal inhibitory concentrations (IC50) = 2.91 μM and 34 μM, respectively) and exhibited only moderate cytotoxicity against HeLa cells (Half-maximal cytotoxic concentration (CC50) = 133 μM and 350 μM, respectively). Free energy calculations reproduced the experimental affinities of the hits for FP-2 and explained the selectivity with respect to hCatK.

GENERAL SIGNIFICANCE:

To the best of our knowledge, HTS07940 stands among the most selective FP-2 inhibitors identified by SBVS reported so far, displaying moderate antiplasmodial activity and low cytotoxicity against human cells. Hence, this compound constitutes a promising lead for the design of more potent and selective FP-2 inhibitors.

KEYWORDS:

Binding mode; Falcipain 2; Inhibition assay; Molecular dynamics; Plasmodium falciparum; Virtual screening

PMID:
30253205
DOI:
10.1016/j.bbagen.2018.09.015
[Indexed for MEDLINE]

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